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New Insight into Cellular and Molecular Bases of Brain Disorders

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (25 November 2022) | Viewed by 14814

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Special Issue Editors

Prof. Dr. Xiong-Jian Luo

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Guest Editor

KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
Interests: psychiatric disorders; schizophrenia; depression; genetics; functional genomics; pathogenesis

Prof. Dr. Chuang Wang

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Guest Editor

School of Medicine, Ningbo University, Ningbo, Zhejiang, China
Interests: psychiatric disorders; genetics

Special Issue Information

Dear Colleagues,

Psychiatric disorders are prevalent mental disorders that affect millions of people worldwide populations. As a leading cause of disability worldwide, psychiatric disorders bring substantial societal costs and economic burden. In the past decade, multiple large-scale genome-wide association studies (GWASs) have been conducted, and numerous risk loci for psychiatric disorders have been reported. However, how the identified risk variants confer the susceptibility of psychiatric disorders remains largely unknown. In this Special Issue, we focus on the cellular and molecular bases of psychiatric disorders. Studies that translate GWAS findings into the cellular and molecular bases of psychiatric disorders are highly encouraged.

Prof. Dr. Xiong-Jian Luo
Prof. Dr. Chuang Wang
Guest Editors

Manuscript Submission Information

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Keywords

psychiatric disorders
schizophrenia
depression
bipolar disorder
anxiety disorder
genetic etiology
cellular and molecular mechanisms
therapeutics

Published Papers (6 papers)

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Research

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15 pages, 1396 KiB

Open AccessArticle

Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells

by Yael Yuhas, Shai Ashkenazi, Eva Berent and Abraham Weizman

Brain Sci. 2022, 12(12), 1703; https://doi.org/10.3390/brainsci12121703 - 12 Dec 2022

Cited by 2 | Viewed by 1319

Abstract

Schizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocarditis, limit its use. We investigated the immunomodulatory effects of clozapine in an astroglial model of neuroinflammation. We thus assessed the effect of clozapine on the production of inflammatory mediators in human-derived astroglial (A172) cells, stimulated with a cytokine mix (TNFα, IL-1β, IFNγ). RT-PCR and ELISA analyses demonstrated that clozapine suppressed gene expression and production of TNFα, IL-1β and IL-8 and increased COX2 mRNA 24 h after stimulation. Clozapine inhibited Akt phosphorylation induced by the cytokine mix at 10 min and 40 min, as assessed by Western blot analysis with anti-pT308Akt antibody. Pretreatment with the Akt inhibitor MK-2206 increased COX2 gene expression in cytokine-stimulated cells, suggesting that Akt inhibition may be involved in COX2 gene expression upregulation. Clozapine may possess dual beneficial effects: inhibiting astroglial production of proinflammatory cytokines, thus attenuating neuroinflammation, and upregulating COX2 expression that may be relevant to improvement of neural functioning while accounting for some of its detrimental effects. Patients with TRS and neuroinflammatory markers may benefit particularly from clozapine treatment. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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25 pages, 6778 KiB

Open AccessArticle

Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice

by Maria Kaare, Mohan Jayaram, Toomas Jagomäe, Katyayani Singh, Kalle Kilk, Kaie Mikheim, Marko Leevik, Este Leidmaa, Jane Varul, Helis Nõmm, Kristi Rähn, Tanel Visnapuu, Mario Plaas, Kersti Lilleväli, Michael K. E. Schäfer, Mari-Anne Philips and Eero Vasar

Brain Sci. 2022, 12(12), 1696; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12121696 - 10 Dec 2022

Cited by 2 | Viewed by 2295

Abstract

In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (NEGR1) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1^−/− mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1^−/− mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1^−/− mice, and escitalopram rescued reduced weight of hippocampi in Negr1^−/− mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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26 pages, 2448 KiB

Open AccessEditor’s ChoiceArticle

Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder

by Ria Gupta, Sidharth Mehan, Pranshul Sethi, Aradhana Prajapati, Abdulrahman Alshammari, Metab Alharbi, Haneen A. Al-Mazroua and Acharan S. Narula

Brain Sci. 2022, 12(3), 342; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12030342 - 02 Mar 2022

Cited by 17 | Viewed by 3532

Abstract

Obsessive-compulsive disorder is a mental disorder characterized by repetitive, unwanted thoughts and behavior due to abnormal neuronal corticostriatal-thalamocortical pathway and other neurochemical changes. Purmorphamine is a smoothened-sonic-hedgehog agonist that has a protective effect against many neurological diseases due to its role in maintaining functional connectivity during CNS development and its anti-inflammatory and antioxidant properties. As part of our current research, we investigated the neuroprotective effects of PUR against behavioral and neurochemical changes in 8-hydroxy-2-(di-n-propylamino)-tetralin-induced obsessive-compulsive disorder in rats. Additionally, the effect of PUR was compared with the standard drug for OCD, i.e., fluvoxamine. The intra-dorsal raphe-nucleus injection of 8-OH-DPAT in rats for seven days significantly showed OCD-like repetitive and compulsive behavior along with increased oxidative stress, inflammation, apoptosis, as well as neurotransmitter imbalance. These alterations were dose-dependently attenuated by long-term purmorphamine treatment at 5 mg/kg and 10 mg/kg i.p. In this study, we assessed the level of various neurochemical parameters in different biological samples, including brain homogenate, blood plasma, and CSF, to check the drug’s effect centrally and peripherally. These effects were comparable to the standard oral treatment withfluvoxamine at 10 mg/kg. However, when fluvoxamine was given in combination with purmorphamine, there was a more significant restoration of these alterations than the individualtreatmentswithfluvoxamine and purmorphamine. All the above findings demonstrate that the neuroprotective effect of purmorphamine in OCD can be strong evidence for developing a new therapeutic target for treating and managing OCD. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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9 pages, 392 KiB

Open AccessCommunication

Deregulatory miRNA-BDNF Network Inferred from Dynamic Expression Changes in Schizophrenia

by Xiaoqian Fu, Yansong Liu, Ancha Baranova and Fuquan Zhang

Brain Sci. 2022, 12(2), 167; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12020167 - 27 Jan 2022

Cited by 6 | Viewed by 2032

Abstract

(1) Background: Brain-derived neurotrophic factor (BDNF) is one of the promising risk genes for schizophrenia (SZ), a disease with prominent dysregulation of miRNA networks. Here, we present a study of miRNA-BDNF co-expression changes in peripheral blood of SZ patients. (2) Methods: The expression levels of the BDNF mRNA and three validated binding miRNAs—miR-124-3p, miR-132-3p, and miR-206—were quantified in the blood of 48 healthy controls and 32 SZ patients before and after 12 weeks of treatment. The co-expression patterns were evaluated in the three groups. (3) Results: The expression levels of BDNF were significantly downregulated in SZ patients compared to the controls. After the treatment, the expression levels of BDNF were upregulated, while the expression levels of the three miRNAs were downregulated. Co-expression analyses showed positive correlations of this network in the SZ patients, while weak negative correlations were observed in the healthy controls. After the 12-week treatment, the overall correlation between BDNF and the three miRNAs reached the levels comparable to the healthy controls. (4) Conclusions: Our findings suggest the involvement of the miRNA-BDNF network in the onset and treatment of SZ. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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18 pages, 2468 KiB

Open AccessEditor’s ChoiceArticle

Multi-Modal Feature Selection with Feature Correlation and Feature Structure Fusion for MCI and AD Classification

by Zhuqing Jiao, Siwei Chen, Haifeng Shi and Jia Xu

Brain Sci. 2022, 12(1), 80; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12010080 - 05 Jan 2022

Cited by 23 | Viewed by 3037

Abstract

Feature selection for multiple types of data has been widely applied in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) classification research. Combining multi-modal data for classification can better realize the complementarity of valuable information. In order to improve the classification performance of feature selection on multi-modal data, we propose a multi-modal feature selection algorithm using feature correlation and feature structure fusion (FC2FS). First, we construct feature correlation regularization by fusing a similarity matrix between multi-modal feature nodes. Then, based on manifold learning, we employ feature matrix fusion to construct feature structure regularization, and learn the local geometric structure of the feature nodes. Finally, the two regularizations are embedded in a multi-task learning model that introduces low-rank constraint, the multi-modal features are selected, and the final features are linearly fused and input into a support vector machine (SVM) for classification. Different controlled experiments were set to verify the validity of the proposed method, which was applied to MCI and AD classification. The accuracy of normal controls versus Alzheimer’s disease, normal controls versus late mild cognitive impairment, normal controls versus early mild cognitive impairment, and early mild cognitive impairment versus late mild cognitive impairment achieve 91.85 ± 1.42%, 85.33 ± 2.22%, 78.29 ± 2.20%, and 77.67 ± 1.65%, respectively. This method makes up for the shortcomings of the traditional multi-modal feature selection based on subjects and fully considers the relationship between feature nodes and the local geometric structure of feature space. Our study not only enhances the interpretation of feature selection but also improves the classification performance, which has certain reference values for the identification of MCI and AD. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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Other

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8 pages, 798 KiB

Open AccessHypothesis

Selection of Olduvai Domains during Evolution: A Role for Primate-Specific Splicing Super-Enhancer and RNA Guanine Quadruplex in Bipartite NBPF Exons

by Igor Vořechovský

Brain Sci. 2022, 12(7), 874; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12070874 - 30 Jun 2022

Viewed by 1486

Abstract

Olduvai protein domains (also known as DUF1220 or NBPF) have undergone the greatest human-specific increase in the copy number of any coding region in the genome. Their repeat number was strongly associated with the evolutionary expansion of brain volumes, neuron counts and cognitive abilities, as well as with disorders of the autistic spectrum. Nevertheless, the domain function and cellular mechanisms underlying the positive selection of Olduvai DNA sequences in higher primates remain obscure. Here, I show that the inclusion of Olduvai exon doublets in mature transcripts is facilitated by a potent splicing enhancer that was created through duplication within the first exon. The enhancer is the strongest among the NBPF transcripts and further promotes the already high splicing activity of the unexpanded first exons of the two-exon domains, safeguarding the expanded Olduvai exon doublets in the mature transcriptome. The duplication also creates a predicted RNA guanine quadruplex that may regulate the access to spliceosomal components of the super-enhancer and influence the splicing of adjacent exons. Thus, positive Olduvai selection during primate evolution is likely to result from a combination of multiple targets in gene expression pathways, including RNA splicing. Full article

(This article belongs to the Special Issue New Insight into Cellular and Molecular Bases of Brain Disorders)

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