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Special Issue "Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles"

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 (31 March 2021).

Special Issue Editor

Prof. Dr. Changjong Moon
E-Mail Website
Guest Editor
College of Veterinary Medicine, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, South Korea
Interests: Behavioral Neuroscience; Cognitive Function; Emotional Regulation; Prefrontal Cortex; Hippocampus; Molecular Neurobiology

Special Issue Information

Dear Colleagues,

Various animal models have played a key role in neurological disorder research. The 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, with a final goal of mechanistically constructed therapeutics which 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, aside from updates concerning previously established animal models, as well as new insights in the molecular mechanisms behind the disorders. This Special Issue intends to present new interesting developments in the field. Articles offering innovative insights in 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, 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

Manuscript Submission Information

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Keywords

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

Published Papers (10 papers)

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Research

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Open AccessArticle
Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia
Int. J. Mol. Sci. 2021, 22(5), 2644; https://doi.org/10.3390/ijms22052644 - 05 Mar 2021
Viewed by 301
Abstract
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of [...] Read more.
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis. Full article
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Open AccessArticle
Transcriptome Sequencing in the Preoptic Region of Rat Dams Reveals a Role of Androgen Receptor in the Control of Maternal Behavior
Int. J. Mol. Sci. 2021, 22(4), 1517; https://doi.org/10.3390/ijms22041517 - 03 Feb 2021
Viewed by 335
Abstract
(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of [...] Read more.
(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of mothers whose pups were taken away immediately after parturition and did not exhibit caring behavior 10 days later. (3) Results: Differentially expressed genes were found and validated by quantitative RT-PCR, among them NACHT and WD repeat domain containing 1 (Nwd1) is known to control androgen receptor (AR) protein levels. The distribution of Nwd1 mRNA and AR was similar in the preoptic area. Therefore, we focused on this steroid hormone receptor and found its reduced protein level in rat dams. To establish the function of AR in maternal behavior, its antagonist was administered intracerebroventricularly into mother rats and increased pup-directed behavior of the animals. (4) Conclusions: AR levels are suppressed in the preoptic area of mothers possibly mediated by altered Nwd1 expression in order to allow sustained high-level care for the pups. Thus, our study first implicated the AR in the control of maternal behaviors. Full article
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Open AccessArticle
Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome
Int. J. Mol. Sci. 2020, 21(23), 9327; https://doi.org/10.3390/ijms21239327 - 07 Dec 2020
Viewed by 639
Abstract
Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, [...] Read more.
Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment. Full article
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Open AccessArticle
Interplay of Prenatal and Postnatal Risk Factors in the Behavioral and Histological Features of a “Two-Hit” Non-Genetic Mouse Model of Schizophrenia
Int. J. Mol. Sci. 2020, 21(22), 8518; https://doi.org/10.3390/ijms21228518 - 12 Nov 2020
Viewed by 450
Abstract
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were [...] Read more.
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia. Full article
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Open AccessArticle
Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice
Int. J. Mol. Sci. 2020, 21(11), 4131; https://doi.org/10.3390/ijms21114131 - 10 Jun 2020
Viewed by 820
Abstract
Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in [...] Read more.
Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus. Full article
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Review

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Open AccessReview
Where and Why Modeling Amyotrophic Lateral Sclerosis
Int. J. Mol. Sci. 2021, 22(8), 3977; https://doi.org/10.3390/ijms22083977 - 12 Apr 2021
Viewed by 290
Abstract
Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates [...] Read more.
Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS. Full article
Open AccessReview
Experimental Model Systems for Understanding Human Axonal Injury Responses
Int. J. Mol. Sci. 2021, 22(2), 474; https://doi.org/10.3390/ijms22020474 - 06 Jan 2021
Viewed by 455
Abstract
Neurons are structurally unique and have dendrites and axons that are vulnerable to injury. Some neurons in the peripheral nervous system (PNS) can regenerate their axons after injuries. However, most neurons in the central nervous system (CNS) fail to do so, resulting in [...] Read more.
Neurons are structurally unique and have dendrites and axons that are vulnerable to injury. Some neurons in the peripheral nervous system (PNS) can regenerate their axons after injuries. However, most neurons in the central nervous system (CNS) fail to do so, resulting in irreversible neurological disorders. To understand the mechanisms of axon regeneration, various experimental models have been utilized in vivo and in vitro. Here, we collate the key experimental models that revealed the important mechanisms regulating axon regeneration and degeneration in different systems. We also discuss the advantages of experimenting with the rodent model, considering the application of these findings in understanding human diseases and for developing therapeutic methods. Full article
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Open AccessReview
Peripheral Nerve Regeneration and Muscle Reinnervation
Int. J. Mol. Sci. 2020, 21(22), 8652; https://doi.org/10.3390/ijms21228652 - 17 Nov 2020
Cited by 3 | Viewed by 944
Abstract
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The [...] Read more.
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration. Full article
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Open AccessReview
Stem Cell-Based Therapies for Parkinson Disease
Int. J. Mol. Sci. 2020, 21(21), 8060; https://doi.org/10.3390/ijms21218060 - 29 Oct 2020
Cited by 2 | Viewed by 853
Abstract
Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis [...] Read more.
Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis of PD is based on the presence of impaired motor features such as asymmetric or unilateral resting tremor, bradykinesia, and rigidity. Nonmotor features including cognitive impairment, sleep disorders, and autonomic dysfunction are also present. No cure for PD has been discovered, and treatment strategies focus on symptomatic management through restoration of dopaminergic activity. However, proposed cell replacement therapies are promising because midbrain dopaminergic neurons have been shown to restore dopaminergic neurotransmission and functionally rescue the dopamine-depleted striatum. In this review, we summarize our current understanding of the molecular pathogenesis of neurodegeneration in PD and discuss the development of new therapeutic strategies that have led to the initiation of exploratory clinical trials. We focus on the applications of stem cells for the treatment of PD and discuss how stem cell research has contributed to an understanding of PD, predicted the efficacy of novel neuroprotective therapeutics, and highlighted what we believe to be the critical areas for future research. Full article
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Open AccessReview
Effects of Ketamine on Rodent Fear Memory
Int. J. Mol. Sci. 2020, 21(19), 7173; https://doi.org/10.3390/ijms21197173 - 28 Sep 2020
Viewed by 853
Abstract
Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder [...] Read more.
Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder (PTSD) remains controversial. To address these concerns, preclinical studies have investigated the effects of ketamine administration on fear memory and stress-related behaviors in laboratory animals. Despite a well-documented line of research examining the effects of ketamine on fear memory, there is a lack of literature reviews on this important topic. Therefore, this review article summarizes the current preclinical literature on ketamine and fear memory with a particular emphasis on the route, dose, and timing of ketamine administration in rodent fear conditioning studies. Additionally, this review describes the molecular mechanisms by which ketamine may impact fear memory and stress-related behaviors. Overall, findings from previous studies are inconsistent in that fear memory may be increased, decreased, or unaltered following ketamine administration in rodents. These conflicting results can be explained by factors such as the route, dose, and timing of ketamine administration; the interaction between ketamine and stress; and individual variability in the rodent response to ketamine. This review also recommends that future preclinical studies utilize a clinically relevant route of administration and account for biological sex differences to improve translation between preclinical and clinical investigations. Full article
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