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Ramadan YN, Alqifari SF, Alshehri K, Alhowiti A, Mirghani H, Alrasheed T, Aljohani F, Alghamdi A, Hetta HF. Microbiome Gut-Brain-Axis: Impact on Brain Development and Mental Health. Mol Neurobiol 2025:10.1007/s12035-025-04846-0. [PMID: 40234288 DOI: 10.1007/s12035-025-04846-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 03/12/2025] [Indexed: 04/17/2025]
Abstract
The current discovery that the gut microbiome, which contains roughly 100 trillion microbes, affects health and disease has catalyzed a boom in multidisciplinary research efforts focused on understanding this relationship. Also, it is commonly demonstrated that the gut and the CNS are closely related in a bidirectional pathway. A balanced gut microbiome is essential for regular brain activities and emotional responses. On the other hand, the CNS regulates the majority of GI physiology. Any disruption in this bidirectional pathway led to a progression of health problems in both directions, neurological and gastrointestinal diseases. In this review, we hope to shed light on the complicated connections of the microbiome-gut-brain axis and the critical roles of gut microbiome in the early development of the brain in order to get a deeper knowledge of microbiome-mediated pathological conditions and management options through rebalancing of gut microbiome.
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Affiliation(s)
- Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Saleh F Alqifari
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Khaled Alshehri
- Department of Internal Medicine (Neurology), Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Amirah Alhowiti
- Department of Family and Community Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Hyder Mirghani
- Department of Internal Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Tariq Alrasheed
- Department of Internal Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Faisal Aljohani
- Division of Medicine and Gastroenterology, Department of Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Abdulaziz Alghamdi
- Department of Medicine, Division of Psychiatry, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
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Ju XD, Zhang PH, Li Q, Bai QY, Hu B, Xu J, Lu C. Peripheral Blood Monocytes as Biomarkers of Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis. Res Child Adolesc Psychopathol 2025; 53:583-595. [PMID: 40053221 DOI: 10.1007/s10802-025-01303-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 04/26/2025]
Abstract
Accumulating evidence implicates immune dysregulation and chronic inflammation in neurodevelopmental disorders (NDDs), often manifesting as abnormal alterations in peripheral blood immune cell levels. The mononuclear phagocyte system, including monocytes and microglia, has been increasingly recognized for its involvement in the pathogenesis of NDDs. However, due to inconsistent findings in the literature, whether monocytes can serve as a reliable biomarker for NDDs remains controversial. To address this issue, we conducted a systematic review and meta-analysis of studies examining monocyte counts in NDD individuals. A comprehensive search was conducted across PubMed, Web of Science, and Scopus databases. Variables extracted for analysis encompassed the author's name, year of study, sample size, patient's age, type of disease, mean, standard deviation of monocytes and sex ratio. A total of 2503 articles were found by searching the three databases. After removed duplicates and screening titles, abstracts, and full texts, 17 articles met the inclusion criteria, and 20 independent studies were included in the meta-analysis. The results indicated significantly increased monocyte counts in 5 type NDDs compared to Typical Development (TD) groups (g = 0.36, 95%CI [0.23, 0.49]). Subgroup analyses revealed no significant differences in monocyte counts across different NDD types, gender, or age. These findings suggest that aberrant alterations in monocyte counts are common in NDD cases, indicating their potential as biomarkers for these conditions. Future research should further investigate the role of monocyte in understanding the mechanisms, early detection, and clinical diagnosis of NDDs.
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Affiliation(s)
- Xing-Da Ju
- School of Psychology, Northeast Normal University, Changchun, China
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China
- Autism Centre of Excellence, Northeast Normal University, Changchun, China
| | - Pai-Hao Zhang
- School of Psychology, Northeast Normal University, Changchun, China
| | - Qiang Li
- School of Psychology, Northeast Normal University, Changchun, China
| | - Qiu-Yu Bai
- Yancheng College of Mechatronic Technology, Yancheng, China
| | - Bo Hu
- School of Psychology, Northeast Normal University, Changchun, China
- School of Social and Behavioral Science, Nanjing University, Nanjing, China
| | - Jing Xu
- School of Life Sciences, Northeast Normal University, Changchun, China
| | - Chang Lu
- School of Psychology, Northeast Normal University, Changchun, China.
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China.
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Dong Z, Zhuo R, Wang Q, Sun Y, Zhou Z, Wu R, Liu Y, Liu M. Kif15 regulates Coro1a + cell migration and phagocytosis in zebrafish after spinal cord injury. Int Immunopharmacol 2025; 146:113874. [PMID: 39709909 DOI: 10.1016/j.intimp.2024.113874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/11/2024] [Accepted: 12/13/2024] [Indexed: 12/24/2024]
Abstract
The role of immune cells is crucial in nerve regeneration following spinal cord injury. Kif15, a member of the kinesin family, has been shown to enhance macrophage phagocytosis. This study investigates the impact of Kif15 deficiency on immune cells in zebrafish with spinal cord injury. Using kif15 morphants in Tg(coro1a:EGFP) zebrafish, we observed increased recruitment of Coro1a+ cells to the injury site, followed by a rapid decline in kif15 morphants. Transcriptome analysis revealed that inflammatory and phagocytic signals were significantly enhanced at 1-hour post-injury (hpi), while MAPK pathways indicated growth at 24 hpi. Enhanced phagocytosis was confirmed using neutral red particles, and the Kif15 inhibitor GW406108X further supported increased migration and phagocytosis in macrophages. Activation of Cdc42 and RhoA was significantly increased, contributing to cell motility and phagocytosis. Additionally, the number of apoptotic cells was reduced in kif15 morphants, suggesting that Kif15 depletion could activate immune cells and efficiently remove apoptotic cells. Our study provides in vivo evidence that Kif15 is involved in immune cell migration and phagocytosis and suggests potential therapeutic roles for Kif15 inhibitors in spinal cord injury treatment.
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Affiliation(s)
- Zhangji Dong
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Run Zhuo
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Qing Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Ying Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Zhihao Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Ronghua Wu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Yan Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China
| | - Mei Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong Jiangsu 226001, China.
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Jay TR, Kang Y, Ouellet-Massicotte V, Micael MKB, Kacouros-Perkins VL, Chen J, Sheehan A, Freeman MR. Developmental and age-related synapse elimination is mediated by glial Croquemort. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.24.600214. [PMID: 39026803 PMCID: PMC11257470 DOI: 10.1101/2024.06.24.600214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit maturation, and that glia use conserved molecules to regulate these processes. Using a high throughput ELISA-based in vivo screening assay, we identify new glial genes that regulate synapse numbers in Drosophila in vivo, including the scavenger receptor ortholog Croquemort (Crq). Crq acts as an essential regulator of glial-dependent synapse elimination during development, with glial Crq loss leading to excess CNS synapses and progressive seizure susceptibility in adults. Loss of Crq in glia also prevents age-related synaptic loss in the adult brain. This work provides new insights into the cellular and molecular mechanisms that underlie synapse development and maintenance across the lifespan, and identifies glial Crq as a key regulator of these processes.
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Kurup D, FitzPatrick AM, Badura A, Serra I. Bridging the gap: neurodevelopmental disorder risks in inborn errors of immunity. Curr Opin Allergy Clin Immunol 2024; 24:472-478. [PMID: 39374040 PMCID: PMC11537469 DOI: 10.1097/aci.0000000000001036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
PURPOSE OF REVIEW The aim of this review is to examine published reports of neurodevelopmental phenotypes in patients with inborn errors of immunity (IEI). We briefly discuss potential interactions between the immune and the central nervous system and the implications of this crosstalk for current clinical management guidelines. RECENT FINDINGS An increasing number of reports have described neurodevelopmental disorders (NDDs) comorbid with immune-mediated signs. However, the prevalence of this association in IEIs remains unknown. SUMMARY IEIs comprise a group of clinically heterogeneous disorders associated with a number of nonimmune comorbidities. Although certain neurological conditions such as microcephaly are recognized as associated features of some IEIs, NDDs are less well described. We reviewed published clinical descriptions of IEIs and found a number of comorbid NDDs in these patients, including autism spectrum disorder (ASD), behavioral deficits, and intellectual disability. Given the lack of uniform assessments for NDDs, we suspect they may be underdiagnosed in IEIs. As NDDs manifest early and can result in life-long cognitive and emotional deficits, which diminish quality of life and increase healthcare utilization, we hope to elucidate relevant pathomechanisms and raise clinician awareness of these comorbidities so appropriate and timely interventions are sought.
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Affiliation(s)
- Devika Kurup
- Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands
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Chen T, Meng H, Fang N, Shi P, Chen M, Liu Q, Lv L, Li W. Age-related changes in behavior profile in male offspring of rats treated with poly I:C-induced maternal immune activation in early gestation. Animal Model Exp Med 2024; 7:914-925. [PMID: 38741390 PMCID: PMC11680485 DOI: 10.1002/ame2.12417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 03/21/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Autism and schizophrenia are environmental risk factors associated with prenatal viral infection during pregnancy. It is still unclear whether behavior phenotypes change at different developmental stages in offspring following the activation of the maternal immune system. METHODS Sprague-Dawley rats received a single caudal vein injection of 10 mg/kg polyinosinic:polycytidylic acid (poly I:C) on gestational day 9 and the offspring were comprehensively tested for behaviors in adolescence and adulthood. RESULTS Maternal serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α were elevated in poly I:C-treated dams. The offspring of maternal poly I:C-induced rats showed increased anxiety, impaired social approach, and progressive impaired cognitive and sensorimotor gating function. CONCLUSION Maternal immune activation led to developmental specificity behavioral impairment in offspring.
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Affiliation(s)
- Tengfei Chen
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Huadan Meng
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Ni Fang
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Peiling Shi
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Mengxue Chen
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Qing Liu
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
| | - Luxian Lv
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
- Henan Province People's HospitalZhengzhouHenanChina
| | - Wenqiang Li
- Henan Mental HospitalThe Second Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
- Henan Key Lab of Biological Psychiatry of Xinxiang Medical UniversityXinxiangChina
- International Joint Research Laboratory for Psychiatry and Neuroscience of HenanXinxiangChina
- Henan Collaborative Innovation Center of Prevention and Treatment of Mental DisorderXinxiang Medical UniversityXinxiangChina
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Wang H, Ma Y, Jin D, Yang X, Xu X. Ulinastatin modulates NLRP3 inflammasome pathway in PTZ-induced epileptic mice: A potential mechanistic insight. Heliyon 2024; 10:e38050. [PMID: 39386862 PMCID: PMC11462202 DOI: 10.1016/j.heliyon.2024.e38050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/03/2024] [Accepted: 09/17/2024] [Indexed: 10/12/2024] Open
Abstract
Objective The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome-driven immune-inflammatory response has been shown to play a critical role in epilepsy progression across multiple studies. While Ulinastatin (UTI), an immunomodulatory agent known to target the NLRP3 pathway in neurological disorders, its implications in epilepsy have not been extensively studied. This investigation aims to explore UTI's role and underlying mechanisms in epilepsy. Methods To assess UTI's effects on epilepsy severity, neuroinflammation, and BBB integrity, a pentylenetetrazole (PTZ)-induced epilepsy model in mice and a co-culture system involving BV2 and HT22 cells stimulated by lipopolysaccharide (LPS) and ATP were employed. Techniques utilized included qPCR, Western blotting, ELISA, immunohistochemistry (IHC) staining, Evans Blue dye extravasation, glutamate assays, the Morris water maze, and Annexin V apoptosis assays. Results In the PTZ model, UTI administration led to a substantial decrease in seizure intensity and susceptibility, inhibited NLRP3 inflammasome activation, reduced neuroinflammatory interactions, lowered hippocampal and systemic inflammatory mediator levels, and improved cognitive performance. Furthermore, UTI upregulated claudin-5 expression, a tight junction protein in the endothelium, and diminished Evans Blue dye leakage, indicating improved BBB integrity. In BV2 and HT22 cell co-culture models, UTI exerted neuroprotective effects by mitigating microglia-mediated neurotoxicity and fostering neuronal recovery. Conclusions The findings demonstrate that UTI exerts transformative regulatory effects on the NLRP3 inflammasome in epilepsy models. This intervention effectively suppresses neuroinflammation, lessens seizure severity and susceptibility, and ameliorates epilepsy-related BBB dysfunction and cognitive impairments.
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Affiliation(s)
- Huan Wang
- Department of Neonatology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yuzhu Ma
- Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dongmei Jin
- Department of Neonatology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xinlei Yang
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiangping Xu
- Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Poli F, Koolen M, Velázquez-Vargas CA, Ramos-Sanchez J, Meyer M, Mars RB, Rommelse N, Hunnius S. Autistic traits foster effective curiosity-driven exploration. PLoS Comput Biol 2024; 20:e1012453. [PMID: 39480751 PMCID: PMC11527316 DOI: 10.1371/journal.pcbi.1012453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 09/03/2024] [Indexed: 11/02/2024] Open
Abstract
Curiosity-driven exploration involves actively engaging with the environment to learn from it. Here, we hypothesize that the cognitive mechanisms underlying exploratory behavior may differ across individuals depending on personal characteristics such as autistic traits. In turn, this variability might influence successful exploration. To investigate this, we collected self- and other-reports of autistic traits from university students, and tested them in an exploration task in which participants could learn the hiding patterns of multiple characters. Participants' prediction errors and learning progress (i.e., the decrease in prediction error) on the task were tracked with a hierarchical delta-rule model. Crucially, participants could freely decide when to disengage from a character and what to explore next. We examined whether autistic traits modulated the relation of prediction errors and learning progress with exploration. We found that participants with lower scores on other-reports of insistence-on-sameness and general autistic traits were less persistent, primarily relying on learning progress during the initial stages of exploration. Conversely, participants with higher scores were more persistent and relied on learning progress in later phases of exploration, resulting in better performance in the task. This research advances our understanding of the interplay between autistic traits and exploration drives, emphasizing the importance of individual traits in learning processes and highlighting the need for personalized learning approaches.
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Affiliation(s)
- Francesco Poli
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom
| | - Maran Koolen
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | | | - Jessica Ramos-Sanchez
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | - Marlene Meyer
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
| | - Rogier B. Mars
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
- Wellcome Centre for Integrative Neuroimaging, Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Nanda Rommelse
- Department of Developmental Psychology, Utrecht University, Utrecht, the Netherlands
| | - Sabine Hunnius
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
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Stone TW, Williams RO. Tryptophan metabolism as a 'reflex' feature of neuroimmune communication: Sensor and effector functions for the indoleamine-2, 3-dioxygenase kynurenine pathway. J Neurochem 2024; 168:3333-3357. [PMID: 38102897 DOI: 10.1111/jnc.16015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/16/2023] [Accepted: 11/08/2023] [Indexed: 12/17/2023]
Abstract
Although the central nervous system (CNS) and immune system were regarded as independent entities, it is now clear that immune system cells can influence the CNS, and neuroglial activity influences the immune system. Despite the many clinical implications for this 'neuroimmune interface', its detailed operation at the molecular level remains unclear. This narrative review focuses on the metabolism of tryptophan along the kynurenine pathway, since its products have critical actions in both the nervous and immune systems, placing it in a unique position to influence neuroimmune communication. In particular, since the kynurenine pathway is activated by pro-inflammatory mediators, it is proposed that physical and psychological stressors are the stimuli of an organismal protective reflex, with kynurenine metabolites as the effector arm co-ordinating protective neural and immune system responses. After a brief review of the neuroimmune interface, the general perception of tryptophan metabolism along the kynurenine pathway is expanded to emphasize this environmentally driven perspective. The initial enzymes in the kynurenine pathway include indoleamine-2,3-dioxygenase (IDO1), which is induced by tissue damage, inflammatory mediators or microbial products, and tryptophan-2,3-dioxygenase (TDO), which is induced by stress-induced glucocorticoids. In the immune system, kynurenic acid modulates leucocyte differentiation, inflammatory balance and immune tolerance by activating aryl hydrocarbon receptors and modulates pain via the GPR35 protein. In the CNS, quinolinic acid activates N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, whereas kynurenic acid is an antagonist: the balance between glutamate, quinolinic acid and kynurenic acid is a significant regulator of CNS function and plasticity. The concept of kynurenine and its metabolites as mediators of a reflex coordinated protection against stress helps to understand the variety and breadth of their activity. It should also help to understand the pathological origin of some psychiatric and neurodegenerative diseases involving the immune system and CNS, facilitating the development of new pharmacological strategies for treatment.
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Affiliation(s)
- Trevor W Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Richard O Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
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Zabihi MR, Akhoondian M, Tamimi P, Ghaderi A, Mazhari SA, Farhadi B, Karkhah S, Ghorbani Vajargah P, Mobayen M, Norouzkhani N, Farzan R. Prediction of immune molecules activity during burn wound healing among elderly patients: in-silico analyses: experimental research. Ann Med Surg (Lond) 2024; 86:3972-3983. [PMID: 38989182 PMCID: PMC11230785 DOI: 10.1097/ms9.0000000000002055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 03/28/2024] [Indexed: 07/12/2024] Open
Abstract
Introduction Burn injuries lead to dysregulation of immune molecules, impacting cellular and humoral immune pathways. This study aims to determine the prediction of immune molecule activity during burn wound healing among elderly patients. Methods The current study utilized the Gene Expression Omnibus (GEO) database to extract the proper gene set. Also, the literature review was conducted in the present study to find immune signatures. The study used the "enrich r" website to identify the biological functions of extracted genes. The critical gene modules related to mortality were identified using the weighted gene co-expression network analysis (WGCNA) R package. Results The appreciated GSE was extracted. According to the data, the most upregulated signatures were related to natural killer (NK) cells, and the most downregulated signatures were associated with M1 macrophages. Also, the results of WGCNA have shown that the most related gene modules (P<107 and score 0.17) to mortality were investigated, and the modules 100 first genes were extracted. Additionally, the enrich r analysis has demonstrated related pathways, including the immune process, including regulation of histamine secreted from mast cell (P<0.05), T helper 17 cell differentiation (P<0.05), and autophagy (P<0.05) were obtained. Finally, by network analysis, the critical gene "B3GNT5" were obtained (degree>ten and "betweenness and centrality">30 were considered). Conclusion The study identified significant changes in macrophage and NK cell expression patterns post-burn injury, linking them to potential improvements in clinical outcomes and wound healing. The gene B3GNT5, associated with mortality, was highlighted as a key marker for prognostic evaluation.
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Affiliation(s)
- Mohammad Reza Zabihi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Akhoondian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pegah Tamimi
- Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliasghar Ghaderi
- Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Bahar Farhadi
- School of Medicine, Islamic Azad University, Mashhad Branch, Mashhad, Iran
| | - Samad Karkhah
- Burn and Regenerative Medicine Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran
| | - Pooyan Ghorbani Vajargah
- Burn and Regenerative Medicine Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammadreza Mobayen
- Burn and Regenerative Medicine Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Narges Norouzkhani
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramyar Farzan
- Department of Plastic & Reconstructive Surgery, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Kohli JS, Linke AC, Martindale IA, Wilkinson M, Kinnear MK, Lincoln AJ, Hau J, Shryock I, Omaleki V, Alemu K, Pedrahita S, Fishman I, Müller R, Carper RA. Associations between atypical intracortical myelin content and neuropsychological functions in middle to older aged adults with ASD. Brain Behav 2024; 14:e3594. [PMID: 38849980 PMCID: PMC11161394 DOI: 10.1002/brb3.3594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/06/2024] [Accepted: 05/23/2024] [Indexed: 06/09/2024] Open
Abstract
INTRODUCTION In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants. METHODS Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio. RESULTS Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function. CONCLUSIONS The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.
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Affiliation(s)
- Jiwandeep S. Kohli
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
- San Diego Joint Doctoral Program in Clinical PsychologySan Diego State University/University of CaliforniaSan DiegoCaliforniaUSA
| | - Annika C. Linke
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Ian A. Martindale
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Molly Wilkinson
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
- San Diego Joint Doctoral Program in Clinical PsychologySan Diego State University/University of CaliforniaSan DiegoCaliforniaUSA
| | - Mikaela K. Kinnear
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Alan J. Lincoln
- California School of Professional PsychologyAlliant International UniversitySan DiegoCaliforniaUSA
| | - Janice Hau
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Ian Shryock
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Vinton Omaleki
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Kalekirstos Alemu
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Stephanie Pedrahita
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Inna Fishman
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Ralph‐Axel Müller
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
| | - Ruth A. Carper
- Brain Development Imaging Laboratories, Department of PsychologySan Diego State UniversitySan DiegoCaliforniaUSA
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12
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Blaylock RL. Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis. Surg Neurol Int 2024; 15:171. [PMID: 38840623 PMCID: PMC11152537 DOI: 10.25259/sni_296_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 06/07/2024] Open
Abstract
Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.
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Affiliation(s)
- Russell L. Blaylock
- Theoretical Neuroscience Research, LLC, Ridgeland, Mississippi, United States
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13
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Ravizza T, Scheper M, Di Sapia R, Gorter J, Aronica E, Vezzani A. mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment. Nat Rev Neurosci 2024; 25:334-350. [PMID: 38531962 DOI: 10.1038/s41583-024-00805-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2024] [Indexed: 03/28/2024]
Abstract
Epilepsy remains a major health concern as anti-seizure medications frequently fail, and there is currently no treatment to stop or prevent epileptogenesis, the process underlying the onset and progression of epilepsy. The identification of the pathological processes underlying epileptogenesis is instrumental to the development of drugs that may prevent the generation of seizures or control pharmaco-resistant seizures, which affect about 30% of patients. mTOR signalling and neuroinflammation have been recognized as critical pathways that are activated in brain cells in epilepsy. They represent a potential node of biological convergence in structural epilepsies with either a genetic or an acquired aetiology. Interventional studies in animal models and clinical studies give strong support to the involvement of each pathway in epilepsy. In this Review, we focus on available knowledge about the pathophysiological features of mTOR signalling and the neuroinflammatory brain response, and their interactions, in epilepsy. We discuss mitigation strategies for each pathway that display therapeutic effects in experimental and clinical epilepsy. A deeper understanding of these interconnected molecular cascades could enhance our strategies for managing epilepsy. This could pave the way for new treatments to fill the gaps in the development of preventative or disease-modifying drugs, thus overcoming the limitations of current symptomatic medications.
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Affiliation(s)
- Teresa Ravizza
- Department of Acute Brain and Cardiovascular Injury, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy
| | - Mirte Scheper
- Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Rossella Di Sapia
- Department of Acute Brain and Cardiovascular Injury, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy
| | - Jan Gorter
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands
| | - Eleonora Aronica
- Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.
| | - Annamaria Vezzani
- Department of Acute Brain and Cardiovascular Injury, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy.
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14
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Moss A, Kuttippurathu L, Srivastava A, Schwaber JS, Vadigepalli R. Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat. Physiol Genomics 2024; 56:283-300. [PMID: 38145287 PMCID: PMC11283910 DOI: 10.1152/physiolgenomics.00073.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023] Open
Abstract
Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits toward a state of dysfunction. Using the female spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, nucleus of the solitary tract (NTS), caudal ventrolateral medulla, and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 wk of age, spanning the prehypertensive stage through extended chronic hypertension. RNA-sequencing data were analyzed using an unbiased, dynamic pattern-based approach that uncovered dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development as well as a cascade of transient dysregulation beginning in the RVLM at the prehypertensive stage that shifts toward the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region-specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occurring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.NEW & NOTEWORTHY Hypertension is a major disease and is the primary risk factor for cardiovascular complications and stroke. The gene expression changes in the central nervous system circuits driving hypertension are understudied. Here, we show that coordinated and region-specific gene expression changes occur in the brainstem autonomic circuits over time during the development of a high blood pressure phenotype in a rat model of human essential hypertension.
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Affiliation(s)
- Alison Moss
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Lakshmi Kuttippurathu
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Ankita Srivastava
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - James S Schwaber
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
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15
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Lin YK, Cai XR, Chen JZ, Hong HJ, Tu K, Chen YL, Du Q. Non-alcoholic fatty liver disease causally affects the brain cortical structure: a Mendelian randomization study. Front Neurosci 2024; 17:1305624. [PMID: 38260009 PMCID: PMC10800802 DOI: 10.3389/fnins.2023.1305624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/13/2023] [Indexed: 01/24/2024] Open
Abstract
Background Reduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with non-alcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure. Methods We used pooled-level data from FinnGen's published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stage-associated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis. Results At the global level, NAFLD reduced SA (beta = -586.72 mm2, se = 217.73, p = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy. Conclusion NAFLD causally affects cortical structures, which supports the presence of an intricate liver-brain axis.
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Affiliation(s)
- Yu-Kai Lin
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Xin-Ran Cai
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Jiang-Zhi Chen
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Hai-Jie Hong
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Kai Tu
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Yan-Ling Chen
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
| | - Qiang Du
- Department of Hepatological Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Medical University Cancer Center, Fuzhou, China
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16
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Rahmatinia M, Mohseni-Bandpei A, Khodagholi F, Abdollahifar MA, Amouei Torkmahalleh M, Hassani Moghaddam M, Hopke PK, Ghavimehr E, Bazzazpour S, Shahsavani A. Exposure to different PM 2.5 extracts induces gliosis and changes behavior in male rats similar to autism spectrum disorders features. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 340:122804. [PMID: 37907193 DOI: 10.1016/j.envpol.2023.122804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/02/2023]
Abstract
Epidemiological studies have documented that exposure to fine particulate matter (PM2.5) could affect neurodevelopment, thereby leading to autism spectrum disorders (ASD). Nevertheless, there is little laboratory data to support this epidemiological evidence. In the current study, we carried out a series of experiments to assess whether developmental exposures to different extracts of PM2.5 can result in ASD-like behavioral, biochemical, and immunohistochemical characteristics in male rat offspring. PM2.5 samples were collected daily for a year, and monthly composites were extracted with an acetone-hexane mixture. The extracts were analyzed for their chemical constituents. Three groups of rats were exposed to the different PM2.5 extracts during pre- and postnatal periods. All exposed groups of rats exhibited typical behavioral features of ASD, including increased repetitive and depression-related behaviors. We also found microglia and astrocytes activation and decreased concentrations of oxytocin (OXT) in the brain regions of exposed rats compared with control rats. Comparing the current results with a prior study, the induced biological effects followed a sequence of whole particles of PM2.5 > organic extract > inorganic extract. These findings indicated that exposure to PM2.5 can elicit ASD-like features in rats and raise concerns about particulate matter as a possible trigger for the induction of ASD in humans; therefore, mitigating the contents of the PAHs and metals could reduce the PM2.5 neurotoxicity.
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Affiliation(s)
- Masoumeh Rahmatinia
- Department of Environmental Health Engineering, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Air Quality and Climate Change Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anoushiravan Mohseni-Bandpei
- Department of Environmental Health Engineering, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Air Quality and Climate Change Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Amin Abdollahifar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Amouei Torkmahalleh
- Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Meysam Hassani Moghaddam
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Philip K Hopke
- Department of Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Ehsan Ghavimehr
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shahriyar Bazzazpour
- Department of Environmental Health Engineering, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Shahsavani
- Department of Environmental Health Engineering, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Air Quality and Climate Change Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Sreenivas N, Maes M, Padmanabha H, Dharmendra A, Chakkera P, Paul Choudhury S, Abdul F, Mullapudi T, Gowda VK, Berk M, Vijay Sagar Kommu J, Debnath M. Comprehensive immunoprofiling of neurodevelopmental disorders suggests three distinct classes based on increased neurogenesis, Th-1 polarization or IL-1 signaling. Brain Behav Immun 2024; 115:505-516. [PMID: 37972879 DOI: 10.1016/j.bbi.2023.11.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/18/2023] [Accepted: 11/11/2023] [Indexed: 11/19/2023] Open
Abstract
Neurodevelopmental disorders (NDDs) are a spectrum of conditions with commonalities as well as differences in terms of phenome, symptomatome, neuropathology, risk factors and underlying mechanisms. Immune dysregulation has surfaced as a major pathway in NDDs. However, it is not known if neurodevelopmental disorders share a common immunopathogenetic mechanism. In this study, we explored the possibility of a shared immune etiology in three early-onset NDDs, namely Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Intellectual Disability Disorder (IDD). A panel of 48 immune pathway-related markers was assayed in 135 children with NDDs, represented by 45 children with ASD, ADHD and IDD in each group, along with 35 typically developing children. The plasma levels of 48 immune markers were analyzed on the Multiplex Suspension Assay platform using Pro Human cytokine 48-plex kits. Based on the cytokine/chemokine/growth factor levels, different immune profiles were computed. The primary characteristics of NDDs are depletion of the compensatory immune-regulatory system (CIRS) (z composite of IL-4, IL-10, sIL-1RA, and sIL-2R), increased interleukin (IL)-1 signaling associated with elevated IL-1α and decreased IL-1-receptor antagonist levels, increased neurogenesis, M1/M2 macrophage polarization and increased IL-4 as well as C-C Motif Chemokine Ligand 2 (CCL2) levels. With a cross-validated sensitivity of 81.8% and specificity of 94.4%, these aberrations seem specific for NDDs. Many immunological abnormalities are shared by ASD, ADHD and IDD, which are distinguished by minor differences in IL-9, IL-17 and CCL12. In contrast, machine learning reveals that NDD group consists of three immunologically distinct clusters, with enhanced neurogenesis, Th-1 polarization, or IL-1 signaling as the defining features. NDD is characterized by immune abnormalities that have functional implications for neurogenesis, neurotoxicity, and neurodevelopment. Using machine learning, NDD patients could be classified into subgroups with qualitatively distinct immune disorders that may serve as novel drug targets for the treatment of NDDs.
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Affiliation(s)
- Nikhitha Sreenivas
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand; Department of Psychiatry, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; Research Center, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea; Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, China
| | - Hansashree Padmanabha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Apoorva Dharmendra
- Department of Child and Adolescent Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Priyanka Chakkera
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Saptamita Paul Choudhury
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Fazal Abdul
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Thrinath Mullapudi
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Vykuntaraju K Gowda
- Department of Paediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Michael Berk
- Deakin University, IMPACT Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry, and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
| | - John Vijay Sagar Kommu
- Department of Child and Adolescent Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India.
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18
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De Simone R, Ajmone-Cat MA, Tartaglione AM, Calamandrei G, Minghetti L. Maternal suboptimal selenium intake and low-level lead exposure affect offspring's microglial immune profile and its reactivity to a subsequent inflammatory hit. Sci Rep 2023; 13:21448. [PMID: 38052845 PMCID: PMC10698039 DOI: 10.1038/s41598-023-45613-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 10/21/2023] [Indexed: 12/07/2023] Open
Abstract
Micronutrients such as selenium (Se) are essentials since prenatal life to support brain and cognitive development. Se deficiency, which affects up to 1 billion people worldwide, can interact with common adverse environmental challenges including (Pb), exacerbating their toxic effects. Exploiting our recently validated rat model of maternal Se restriction and developmental low Pb exposure, our aims were to investigate: (i) the early consequences of suboptimal Se intake and low-Pb exposure on neuroinflammation in neonates' whole brains; (ii) the potential priming effect of suboptimal Se and low-Pb exposure on offspring's glial reactivity to a further inflammatory hit. To these aims female rats were fed with suboptimal (0.04 mg/kg; Subopt) and optimal (0.15 mg/kg; Opt) Se dietary levels throughout pregnancy and lactation and exposed or not to environmentally relevant Pb dose in drinking water (12.5 µg/mL) since 4 weeks pre-mating. We found an overall higher basal expression of inflammatory markers in neonatal brains, as well as in purified microglia and organotypic hippocampal slice cultures, from the Subopt Se offspring. Subopt/Pb cultures were highly activated than Subopt cultures and showed a higher susceptibility to the inflammatory challenge lipopolysaccharide than cultures from the Opt groups. We demonstrate that even a mild Se deficiency and low-Pb exposure during brain development can influence the neuroinflammatory tone of microglia, exacerbate the toxic effects of Pb and prime microglial reactivity to subsequent inflammatory stimuli. These neuroinflammatory changes may be responsible, at least in part, for adverse neurodevelopmental outcomes.
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Affiliation(s)
- R De Simone
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy.
| | - M A Ajmone-Cat
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - A M Tartaglione
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - G Calamandrei
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161, Rome, Italy
| | - L Minghetti
- Research Coordination and Support Service, Istituto Superiore di Sanità, 00161, Rome, Italy
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19
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Halepoto DM, AL-Ayadhi LY, Alhowikan AM, Elamin NE. Role of autoimmunity in Neuronal damage in children with Autism spectrum disorder. Pak J Med Sci 2023; 39:1858-1864. [PMID: 37936741 PMCID: PMC10626070 DOI: 10.12669/pjms.39.6.6804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 04/10/2023] [Accepted: 04/24/2023] [Indexed: 11/09/2023] Open
Abstract
"Autism spectrum disorder (ASD) is complex neurodevelopmental disorder characterized by impairments in three core behavioral: social deficits, impaired communication, and repetitive behaviors." There is developing indication and emerging data that irregular autoimmune responses to the central nervous system may play a pathogenic role in patients with autism spectrum disorder." The aim of this review was to discuss the updated research carried out at Autism research and treatment center, King Saud University, Riyadh, Kingdom of Saudi Arabia particularly on the role of autoimmunity in Autism spectrum disorder. This review also present state of information available about the role of autoimmunity biomarkers involved in the neuronal damage of central nervous system in autistic children. The systematic literature search was carried out using Google Scholar, Science direct and PubMed databases on the role of autoimmunity in autism and reviewed all relevant articles published in peer reviewed journals by Autism research and treatment center, King Saud University, Riyadh, Kingdom of Saudi Arabia till April, 2022. We searched relevant articles using key words Autism spectrum disorder, Autoimmunity, Neuroinflamation and Central nervous system. This review revealed that plasma levels of autoimmunity related factors/ markers were altered in patients with autism. Significant change in blood markers in subjects with ASD may resulted in several years of decreased neutrotrophic support along with increasing impairment in relationship with down-regulated inflammation that may play a role in the ASD. Overall, the role of autoimmunity in ASD subjects with excess of anti-brain antibodies suggest that in some patients, autoantibodies that target the CNS may be pathological factor in neuronal growth in autistic children. Large cohort studies with well-defined and specially pheno typed autistic groups and matched healthy controls are required to examine the role of autoantibodies in the pathology of subjects with ASD.
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Affiliation(s)
- Dost Muhammad Halepoto
- Dr. Dost Muhammad Halepoto, PhD. Autism Research and Treatment center, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Laila Yousif AL-Ayadhi
- Dr. Laila Yousif AL-Ayadhi, PhD. Autism Research and Treatment center, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Abdulrahman Mohammed Alhowikan
- Dr. Abdulrahman Mohammed Alhowikan, PhD. Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Nadra Elyass Elamin
- Dr. Nadra Elyass Elamin, PhD. Autism Research and Treatment Center, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
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Mancini M, Natoli S, Gardoni F, Di Luca M, Pisani A. Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19. Int J Mol Sci 2023; 24:ijms24065618. [PMID: 36982693 PMCID: PMC10056044 DOI: 10.3390/ijms24065618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/09/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.
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Affiliation(s)
- Maria Mancini
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy;
- IRCCS Mondino Foundation, 27100 Pavia, Italy
| | - Silvia Natoli
- Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
- IRCCS Maugeri Pavia, 27100 Pavia, Italy
| | - Fabrizio Gardoni
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20133 Milan, Italy; (F.G.); (M.D.L.)
| | - Monica Di Luca
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20133 Milan, Italy; (F.G.); (M.D.L.)
| | - Antonio Pisani
- Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy;
- IRCCS Mondino Foundation, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-0382-380-247
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21
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Makowski C, Wang H, Srinivasan A, Qi A, Qiu Y, van der Meer D, Frei O, Zou J, Visscher P, Yang J, Chen CH. Larger cerebral cortex is genetically correlated with greater frontal area and dorsal thickness. Proc Natl Acad Sci U S A 2023; 120:e2214834120. [PMID: 36893272 PMCID: PMC10089183 DOI: 10.1073/pnas.2214834120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/18/2023] [Indexed: 03/11/2023] Open
Abstract
Human cortical expansion has occurred non-uniformly across the brain. We assessed the genetic architecture of cortical global expansion and regionalization by comparing two sets of genome-wide association studies of 24 cortical regions with and without adjustment for global measures (i.e., total surface area, mean cortical thickness) using a genetically informed parcellation in 32,488 adults. We found 393 and 756 significant loci with and without adjusting for globals, respectively, where 8% and 45% loci were associated with more than one region. Results from analyses without adjustment for globals recovered loci associated with global measures. Genetic factors that contribute to total surface area of the cortex particularly expand anterior/frontal regions, whereas those contributing to thicker cortex predominantly increase dorsal/frontal-parietal thickness. Interactome-based analyses revealed significant genetic overlap of global and dorsolateral prefrontal modules, enriched for neurodevelopmental and immune system pathways. Consideration of global measures is important in understanding the genetic variants underlying cortical morphology.
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Affiliation(s)
- Carolina Makowski
- Department of Radiology, University of California San Diego, La Jolla, CA92093
| | - Hao Wang
- Department of Radiology, University of California San Diego, La Jolla, CA92093
| | - Anjali Srinivasan
- Department of Radiology, University of California San Diego, La Jolla, CA92093
| | - Anna Qi
- Department of Radiology, University of California San Diego, La Jolla, CA92093
| | - Yuqi Qiu
- School of Statistics, East China Normal University, Shanghai20050, China
| | - Dennis van der Meer
- Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, University of Oslo, Oslo0450, Norway
| | - Oleksandr Frei
- Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, University of Oslo, Oslo0450, Norway
| | - Jingjing Zou
- Division of Biostatistics and Bioinformatics, University of California San Diego, La Jolla, CA92093
| | - Peter M. Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD4072, Australia
| | - Jian Yang
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang310024, China
| | - Chi-Hua Chen
- Department of Radiology, University of California San Diego, La Jolla, CA92093
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22
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Debnath M, Berk M. Is paternal immune activation just as important as maternal immune activation? Time to rethink the bi-parental immune priming of neurodevelopmental model of schizophrenia. Med Hypotheses 2023. [DOI: 10.1016/j.mehy.2023.111059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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23
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Accelerated epigenetic aging at birth interacts with parenting hostility to predict child temperament and subsequent psychological symptoms. Dev Psychopathol 2023; 35:109-118. [PMID: 34620266 DOI: 10.1017/s0954579421000614] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In an effort to elucidate new factors that may contribute to developmental psychopathology, the current study examined whether accelerated epigenetic aging at birth related to children's differential susceptibility to the effects of aversive parenting on early emerging mental health risk. Using data from a multiethnic birth cohort, the interaction between Horvath's methylation age in umbilical cord blood and hostile parenting behaviors was examined in relation to perceptions of infant's temperament at 6 months and to children's psychological symptoms at 3 years in 154 families. Results broadly revealed that children with higher levels of accelerated methylation aging evinced more unpredictable temperaments and more psychological symptoms if their mothers reported more hostile parenting, but showed fewer difficulties if mothers engaged in less hostile parenting; children with lower levels of accelerated methylation age did not show associations between hostility and temperament or psychological symptoms. Effects were not accounted for by gestational age at birth, demographic factors, or the distribution of cell subtypes. These findings suggest that accelerated epigenetic age may function as a form of differential susceptibility, signaling increased risk for psychopathology in more aversive contexts but decreased risk in less aversive early environments. Taken together, they point to a novel biological process to consider within risk for psychopathology.
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24
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Webster MJ. Infections, Inflammation, and Psychiatric Illness: Review of Postmortem Evidence. Curr Top Behav Neurosci 2023; 61:35-48. [PMID: 35505055 DOI: 10.1007/7854_2022_362] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
While there is an abundance of epidemiological evidence implicating infectious agents in the etiology of severe mental illnesses, postmortem studies have not yet detected an increased incidence of microbial nucleic acid or proteins in the brains of people with mental illness. Nevertheless, abnormally expressed immune and inflammatory markers have consistently been found in the postmortem brain of patients with schizophrenia and mood disorders. Some of these abnormalities may be the result of an infection in utero or early in life that not only impacted the developing immune system but also the developing neurons of the brain. Some of the immune markers that are consistently found to be upregulated in schizophrenia implicate a possible viral infection and the blood brain barrier in the etiology and neuropathology of the disorder.
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25
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Keil-Stietz K, Lein PJ. Gene×environment interactions in autism spectrum disorders. Curr Top Dev Biol 2022; 152:221-284. [PMID: 36707213 PMCID: PMC10496028 DOI: 10.1016/bs.ctdb.2022.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
There is credible evidence that environmental factors influence individual risk and/or severity of autism spectrum disorders (hereafter referred to as autism). While it is likely that environmental chemicals contribute to the etiology of autism via multiple mechanisms, identifying specific environmental factors that confer risk for autism and understanding how they contribute to the etiology of autism has been challenging, in part because the influence of environmental chemicals likely varies depending on the genetic substrate of the exposed individual. Current research efforts are focused on elucidating the mechanisms by which environmental chemicals interact with autism genetic susceptibilities to adversely impact neurodevelopment. The goal is to not only generate insights regarding the pathophysiology of autism, but also inform the development of screening platforms to identify specific environmental factors and gene×environment (G×E) interactions that modify autism risk. Data from such studies are needed to support development of intervention strategies for mitigating the burden of this neurodevelopmental condition on individuals, their families and society. In this review, we discuss environmental chemicals identified as putative autism risk factors and proposed mechanisms by which G×E interactions influence autism risk and/or severity using polychlorinated biphenyls (PCBs) as an example.
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Affiliation(s)
- Kimberly Keil-Stietz
- Department of Comparative Biosciences, University of Wisconsin-Madison, School of Veterinary Medicine, Madison, WI, United States
| | - Pamela J Lein
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, United States.
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26
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Bucknor MC, Gururajan A, Dale RC, Hofer MJ. A comprehensive approach to modeling maternal immune activation in rodents. Front Neurosci 2022; 16:1071976. [PMID: 36590294 PMCID: PMC9800799 DOI: 10.3389/fnins.2022.1071976] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Prenatal brain development is a highly orchestrated process, making it a very vulnerable window to perturbations. Maternal stress and subsequent inflammation during pregnancy leads to a state referred to as, maternal immune activation (MIA). If persistent, MIA can pose as a significant risk factor for the manifestation of neurodevelopmental disorders (NDDs) such as autism spectrum disorder and schizophrenia. To further elucidate this association between MIA and NDD risk, rodent models have been used extensively across laboratories for many years. However, there are few uniform approaches for rodent MIA models which make not only comparisons between studies difficult, but some established approaches come with limitations that can affect experimental outcomes. Here, we provide researchers with a comprehensive review of common experimental variables and potential limitations that should be considered when designing an MIA study based in a rodent model. Experimental variables discussed include: innate immune stimulation using poly I:C and LPS, environmental gestational stress paradigms, rodent diet composition and sterilization, rodent strain, neonatal handling, and the inclusion of sex-specific MIA offspring analyses. We discuss how some aspects of these variables have potential to make a profound impact on MIA data interpretation and reproducibility.
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Affiliation(s)
- Morgan C. Bucknor
- School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Anand Gururajan
- The Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia
| | - Russell C. Dale
- The Children’s Hospital at Westmead, Kids Neuroscience Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Markus J. Hofer
- School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
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27
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Kang N, Shin W, Jung S, Bang M, Lee SH. The Effect of TNF-alpha rs1800629 Polymorphism on White Matter Structures and Memory Function in Patients With Schizophrenia: A Pilot Study. Psychiatry Investig 2022; 19:1027-1036. [PMID: 36588437 PMCID: PMC9806513 DOI: 10.30773/pi.2021.0326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE This study investigated the effect of TNF-α rs1800629 polymorphism on white matter integrity and memory function in patients with schizophrenia. METHODS Fifty-five participants with schizophrenia were enrolled in this study. They were genotyped for TNF-α rs1800629 polymorphism and underwent diffusion tensor imaging. Memory function was assessed using the Rey-Kim memory test. Participants with schizophrenia were grouped into GG homozygotes and A-allele carriers. RESULTS Compared to GG homozygotes, A-allele carriers had significantly lower scores for immediate and delayed recall and recognition of verbal memory and showed significantly lower fractional anisotropy in extensive brain regions. Lower total scores in immediate and delayed recall of verbal memory, immediate recall of visual memory, and figure copy of visual memory were significantly correlated with decreased mean fractional anisotropy in the white matter tracts of the corresponding brain regions. CONCLUSION Our findings suggest that the A-allele, which is associated with higher levels of TNF-α expression, correlates with lower connectivity of the fronto-temporal white matter compared to that in GG homozygotes. Impaired fronto-temporal connectivity may be associated with genetic vulnerability to schizophrenia, leading to verbal and visual memory deficits in patients with schizophrenia.
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Affiliation(s)
- Naok Kang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Wonsuk Shin
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sra Jung
- Department of Psychiatry, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Minji Bang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
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28
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Stone TW, Clanchy FIL, Huang YS, Chiang NY, Darlington LG, Williams RO. An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front Neurosci 2022; 16:1002004. [PMID: 36507331 PMCID: PMC9729788 DOI: 10.3389/fnins.2022.1002004] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/31/2022] [Indexed: 11/25/2022] Open
Abstract
Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.
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Affiliation(s)
- Trevor W. Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom,*Correspondence: Trevor W. Stone,
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Nien-Yi Chiang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - L. Gail Darlington
- Department of Internal Medicine, Ashtead Hospital, Ashtead, United Kingdom
| | - Richard O. Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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29
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Jiang CC, Lin LS, Long S, Ke XY, Fukunaga K, Lu YM, Han F. Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications. Signal Transduct Target Ther 2022; 7:229. [PMID: 35817793 PMCID: PMC9273593 DOI: 10.1038/s41392-022-01081-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder which has strong genetic basis. Despite the rapidly rising incidence of autism, little is known about its aetiology, risk factors, and disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism. Over the last two decades, there have been remarkable advances in genetics, with hundreds of genes identified and validated as being associated with a high risk for autism. The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism. Efforts have been devoted to exploring the behavioural functions, key pathological mechanisms and potential treatments of autism. Here, as we highlight in this review, emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription, translation, synaptic transmission, epigenetics and immunoinflammatory responses. This involvement has important implications for the discovery of precise molecular targets for autism. Moreover, we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular, cellular, neural circuit, and neurobehavioural aspects. Finally, the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.
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Affiliation(s)
- Chen-Chen Jiang
- International Joint Laboratory for Drug Target of Critical Illnesses; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Li-Shan Lin
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China
| | - Sen Long
- Department of Pharmacy, Hangzhou Seventh People's Hospital, Mental Health Center Zhejiang University School of Medicine, Hangzhou, 310013, China
| | - Xiao-Yan Ke
- Child Mental Health Research Center, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Kohji Fukunaga
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Ying-Mei Lu
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
| | - Feng Han
- International Joint Laboratory for Drug Target of Critical Illnesses; Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
- Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, China.
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30
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Blondel S, Strazielle N, Amara A, Guy R, Bain C, Rose A, Guibaud L, Tiribelli C, Gazzin S, Ghersi-Egea JF. Vascular network expansion, integrity of blood-brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat. Fluids Barriers CNS 2022; 19:47. [PMID: 35672829 PMCID: PMC9172137 DOI: 10.1186/s12987-022-00332-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/20/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood-brain barrier and the choroidal blood-CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood-brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia. METHODS Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes. RESULTS In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood-brain and blood-CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide. CONCLUSION The data highlight developmental specificities of the blood-brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice.
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Affiliation(s)
| | - Nathalie Strazielle
- Brain-i, Lyon, France
- Fluid Team Lyon Neurosciences Research Center, INSERM U1028, CNRS UMR5292, Lyon University, Bron, France
| | - Amel Amara
- Fluid Team Lyon Neurosciences Research Center, INSERM U1028, CNRS UMR5292, Lyon University, Bron, France
| | - Rainui Guy
- BIP Facility, Lyon Neurosciences Research Center, Bron, France
| | | | | | - Laurent Guibaud
- Fluid Team Lyon Neurosciences Research Center, INSERM U1028, CNRS UMR5292, Lyon University, Bron, France
| | - Claudio Tiribelli
- Fondazione Italiana Fegato-Onlus, AREA Science Park, Basovizza, Trieste, Italy
| | - Silvia Gazzin
- Fondazione Italiana Fegato-Onlus, AREA Science Park, Basovizza, Trieste, Italy
| | - Jean-François Ghersi-Egea
- BIP Facility, Lyon Neurosciences Research Center, Bron, France.
- Fluid Team Lyon Neurosciences Research Center, INSERM U1028, CNRS UMR5292, Lyon University, Bron, France.
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31
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Komada M, Nishimura Y. Epigenetics and Neuroinflammation Associated With Neurodevelopmental Disorders: A Microglial Perspective. Front Cell Dev Biol 2022; 10:852752. [PMID: 35646933 PMCID: PMC9133693 DOI: 10.3389/fcell.2022.852752] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/22/2022] [Indexed: 12/15/2022] Open
Abstract
Neuroinflammation is a cause of neurodevelopmental disorders such as autism spectrum disorders, fetal alcohol syndrome, and cerebral palsy. Converging lines of evidence from basic and clinical sciences suggest that dysregulation of the epigenetic landscape, including DNA methylation and miRNA expression, is associated with neuroinflammation. Genetic and environmental factors can affect the interaction between epigenetics and neuroinflammation, which may cause neurodevelopmental disorders. In this minireview, we focus on neuroinflammation that might be mediated by epigenetic dysregulation in microglia, and compare studies using mammals and zebrafish.
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Affiliation(s)
- Munekazu Komada
- Mammalian Embryology, Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
| | - Yuhei Nishimura
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan
- *Correspondence: Yuhei Nishimura,
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Abstract
Immunity could be viewed as the common factor in neurodevelopmental disorders and cancer. The immune and nervous systems coevolve as the embryo develops. Immunity can release cytokines that activate MAPK signaling in neural cells. In specific embryonic brain cell types, dysregulated signaling that results from germline or embryonic mutations can promote changes in chromatin organization and gene accessibility, and thus expression levels of essential genes in neurodevelopment. In cancer, dysregulated signaling can emerge from sporadic somatic mutations during human life. Neurodevelopmental disorders and cancer share similarities. In neurodevelopmental disorders, immunity, and cancer, there appears an almost invariable involvement of small GTPases (e.g., Ras, RhoA, and Rac) and their pathways. TLRs, IL-1, GIT1, and FGFR signaling pathways, all can be dysregulated in neurodevelopmental disorders and cancer. Although there are signaling similarities, decisive differentiating factors are timing windows, and cell type specific perturbation levels, pointing to chromatin reorganization. Finally, we discuss drug discovery.
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Affiliation(s)
- Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Corresponding author
| | - Chung-Jung Tsai
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
| | - Hyunbum Jang
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
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33
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Joyce EE, Chavarro JE, Rando J, Song AY, Croen LA, Fallin MD, Hertz‐Picciotto I, Schmidt RJ, Volk H, Newschaffer CJ, Lyall K. Prenatal exposure to pesticide residues in the diet in association with child autism-related traits: Results from the EARLI study. Autism Res 2022; 15:957-970. [PMID: 35261202 PMCID: PMC9090949 DOI: 10.1002/aur.2698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/31/2022]
Abstract
Prior work has suggested associations between prenatal exposure to several classes of pesticides and child autism spectrum disorder (ASD). We examined a previously developed pesticide residue burden score (PRBS) and intake of high pesticide residue foods in association with ASD-related traits. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 256), a cohort following mothers who previously had a child with ASD through a subsequent pregnancy and that child's development. ASD-related traits were captured according to total Social Responsiveness Scale (SRS) scores at age 3 (mean raw total SRS score = 35.8). Dietary intake was assessed through a food frequency questionnaire collected during pregnancy. We also incorporated organic intake and fatty foods in modified versions of the PRBS. Associations between high-residue fruit and vegetable intake, the overall PRBS and modified versions of it, and SRS scores were assessed using multivariable linear regression. Overall, we did not observe associations between pesticide residues in foods and ASD-related outcomes, and modified versions of the PRBS yielded similar findings. However, reductions in ASD-related traits were observed with higher overall fruit and vegetable intake (adjusted estimates for Q4 vs. Q1: β -12.76, 95%CI -27.8, 2.3). Thus, findings from this high familial probability cohort did not suggest relationships between pesticide residues in the diet according to the PRBS and ASD-related traits. Beneficial effects of fruit and vegetable intake may influence these relationships. Future work should consider fruit and vegetable intake in association with ASD-related outcomes. LAY SUMMARY: Diet is the main source of exposure to most pesticides in use today. In this study, we examined the relationship between pesticide exposure from residues in the diet during pregnancy and child autism-related traits. We found that these pesticide residues from the diet were not related to child autism-related outcomes at age three. However, higher prenatal fruit and vegetable intake was associated with reductions in child autism-related traits.
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Affiliation(s)
- Emily E. Joyce
- Dornsife School of Public Health, Department of Epidemiology and BiostatisticsDrexel UniversityPhiladelphiaPennsylvaniaUSA
| | - Jorge E. Chavarro
- Department of NutritionHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | - Juliette Rando
- A.J. Drexel Autism InstituteDrexel UniversityPhiladelphiaPennsylvaniaUSA
| | - Ashley Y. Song
- Department of Mental HealthJohns HopkinsBaltimoreMarylandUSA
| | - Lisa A. Croen
- Division of ResearchKaiser Permanente Northern CaliforniaOaklandCaliforniaUSA
| | | | - Irva Hertz‐Picciotto
- Department of Public Health SciencesUniversity of CaliforniaDavisCaliforniaUSA
- MIND InstituteSacramentoCAUSA
| | - Rebecca J. Schmidt
- Department of Public Health SciencesUniversity of CaliforniaDavisCaliforniaUSA
- MIND InstituteSacramentoCAUSA
| | - Heather Volk
- Department of Mental HealthJohns HopkinsBaltimoreMarylandUSA
| | - Craig J. Newschaffer
- College of Health and Human DevelopmentPenn State, University Park, State CollegePennsylvaniaUSA
| | - Kristen Lyall
- Dornsife School of Public Health, Department of Epidemiology and BiostatisticsDrexel UniversityPhiladelphiaPennsylvaniaUSA
- A.J. Drexel Autism InstituteDrexel UniversityPhiladelphiaPennsylvaniaUSA
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Dash S, Syed YA, Khan MR. Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders. Front Cell Dev Biol 2022; 10:880544. [PMID: 35493075 PMCID: PMC9048050 DOI: 10.3389/fcell.2022.880544] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.
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Affiliation(s)
- Somarani Dash
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Yasir Ahmed Syed
- School of Biosciences and Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff, United Kingdom
| | - Mojibur R. Khan
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- *Correspondence: Mojibur R. Khan,
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García-Juárez M, Camacho-Morales A. Defining the role of anti- and pro-inflammatory outcomes of Interleukin-6 in mental health. Neuroscience 2022; 492:32-46. [DOI: 10.1016/j.neuroscience.2022.03.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/03/2022] [Accepted: 03/16/2022] [Indexed: 01/03/2023]
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Velloso FJ, Wadhwa A, Kumari E, Carcea I, Gunal O, Levison SW. Modestly increasing systemic interleukin-6 perinatally disturbs secondary germinal zone neurogenesis and gliogenesis and produces sociability deficits. Brain Behav Immun 2022; 101:23-36. [PMID: 34954074 PMCID: PMC8885860 DOI: 10.1016/j.bbi.2021.12.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/07/2021] [Accepted: 12/18/2021] [Indexed: 12/14/2022] Open
Abstract
Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with the developmental origins of psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3-6 when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼ 50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼ 30% less time socially engaging with sexually receptive females and produced ∼ 50% fewer ultrasonic vocalizations during mating. They also engaged ∼ 50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.
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Affiliation(s)
- Fernando Janczur Velloso
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
| | - Anna Wadhwa
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA 07103
| | - Ekta Kumari
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA 07103
| | - Ioana Carcea
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
| | - Ozlem Gunal
- Department of Psychiatry, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
| | - Steven W. Levison
- Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA 07103,Correspondence should be addressed to: Steven W. Levison, PhD, Department Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, 205 S. Orange Ave, Newark, NJ 07103, Phone: 973-972-5162;
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Kim J, Erice C, Rohlwink UK, Tucker EW. Infections in the Developing Brain: The Role of the Neuro-Immune Axis. Front Neurol 2022; 13:805786. [PMID: 35250814 PMCID: PMC8891478 DOI: 10.3389/fneur.2022.805786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/24/2022] [Indexed: 01/02/2023] Open
Abstract
Central nervous system (CNS) infections occur more commonly in young children than in adults and pose unique challenges in the developing brain. This review builds on the distinct vulnerabilities in children's peripheral immune system (outlined in part 1 of this review series) and focuses on how the developing brain responds once a CNS infection occurs. Although the protective blood-brain barrier (BBB) matures early, pathogens enter the CNS and initiate a localized innate immune response with release of cytokines and chemokines to recruit peripheral immune cells that contribute to the inflammatory cascade. This immune response is initiated by the resident brain cells, microglia and astrocytes, which are not only integral to fighting the infection but also have important roles during normal brain development. Additionally, cytokines and other immune mediators such as matrix metalloproteinases from neurons, glia, and endothelial cells not only play a role in BBB permeability and peripheral cell recruitment, but also in brain maturation. Consequently, these immune modulators and the activation of microglia and astrocytes during infection adversely impact normal neurodevelopment. Perturbations to normal brain development manifest as neurodevelopmental and neurocognitive impairments common among children who survive CNS infections and are often permanent. In part 2 of the review series, we broadly summarize the unique challenges CNS infections create in a developing brain and explore the interaction of regulators of neurodevelopment and CNS immune response as part of the neuro-immune axis.
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Affiliation(s)
- John Kim
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Clara Erice
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Ursula K. Rohlwink
- Faculty of Health Sciences, Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Elizabeth W. Tucker
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Ganguli S, Chavali PL. Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment. Front Neurosci 2021; 15:771557. [PMID: 34858132 PMCID: PMC8631423 DOI: 10.3389/fnins.2021.771557] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/18/2021] [Indexed: 12/22/2022] Open
Abstract
Intrauterine viral infections during pregnancy by pathogens such as Zika virus, Cytomegalovirus, Rubella and Herpes Simplex virus can lead to prenatal as well as postnatal neurodevelopmental disorders. Although maternal viral infections are common during pregnancy, viruses rarely penetrate the trophoblast. When they do cross, viruses can cause adverse congenital health conditions for the fetus. In this context, maternal inflammatory responses to these neurotropic pathogens play a significant role in negatively affecting neurodevelopment. For instance, intrauterine inflammation poses an increased risk of neurodevelopmental disorders such as microcephaly, schizophrenia, autism spectrum disorder, cerebral palsy and epilepsy. Severe inflammatory responses have been linked to stillbirths, preterm births, abortions and microcephaly. In this review, we discuss the mechanistic basis of how immune system shapes the landscape of the brain and how different neurotropic viral pathogens evoke inflammatory responses. Finally, we list the consequences of neuroinflammation on fetal brain development and discuss directions for future research and intervention strategies.
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Affiliation(s)
- Sourav Ganguli
- CSIR-Center for Cellular and Molecular Biology, Hyderabad, India.,Academy of Scientific and Innovative Research (AcCSIR), Ghaziabad, India
| | - Pavithra L Chavali
- CSIR-Center for Cellular and Molecular Biology, Hyderabad, India.,Academy of Scientific and Innovative Research (AcCSIR), Ghaziabad, India
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Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder. J Autism Dev Disord 2021; 52:3919-3932. [PMID: 34505185 PMCID: PMC9349096 DOI: 10.1007/s10803-021-05271-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2021] [Indexed: 12/25/2022]
Abstract
Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.
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40
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Abstract
Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and regulating stress responses throughout the life course. Epigenetic reprogramming in the hippocampus and the hypothalamus play an important role in adapting genome function to experiences and exposures during the perinatal and early life periods and setting up stable phenotypic outcomes. Epigenetic programming during development enables one genome to express multiple cell type identities. The most proximal epigenetic mark to DNA is a covalent modification of the DNA itself by enzymatic addition of methyl moieties. Cell-type-specific DNA methylation profiles are generated during gestational development and define cell and tissue specific phenotypes. Programming of neuronal phenotypes and sex differences in the hypothalamus is achieved by developmentally timed rearrangement of DNA methylation profiles. Similarly, other stations in the life trajectory such as puberty and aging involve predictable and scheduled reorganization of DNA methylation profiles. DNA methylation and other epigenetic marks are critical for maintaining cell-type identity in the brain, across the body, and throughout life. Data that have emerged in the last 15 years suggest that like its role in defining cell-specific phenotype during development, DNA methylation might be involved in defining experiential identities, programming similar genes to perform differently in response to diverse experiential histories. Early life stress impact on lifelong phenotypes is proposed to be mediated by DNA methylation and other epigenetic marks. Epigenetic marks, as opposed to genetic mutations, are reversible by either pharmacological or behavioral strategies and therefore offer the potential for reversing or preventing disease including behavioral and mental health disorders. This chapter discusses data testing the hypothesis that DNA methylation modulations of the HPA axis mediate the impact of early life stress on lifelong behavioral and physical phenotypes.
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Affiliation(s)
- Moshe Szyf
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
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41
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Patel RT, Gallamoza BM, Kulkarni P, Sherer ML, Haas NA, Lemanski E, Malik I, Hekmatyar K, Parcells MS, Schwarz JM. An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach. Viruses 2021; 13:v13061123. [PMID: 34207958 PMCID: PMC8230645 DOI: 10.3390/v13061123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/26/2021] [Accepted: 06/03/2021] [Indexed: 12/20/2022] Open
Abstract
Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.
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Affiliation(s)
- Rita T. Patel
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (B.M.G.); (N.A.H.); (E.L.); (J.M.S.)
- Correspondence:
| | - Brennan M. Gallamoza
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (B.M.G.); (N.A.H.); (E.L.); (J.M.S.)
| | - Praveen Kulkarni
- Center for Translational Neuroimaging, Department of Psychology, Northeastern University, Boston, MA 02115, USA;
| | - Morgan L. Sherer
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA;
| | - Nicole A. Haas
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (B.M.G.); (N.A.H.); (E.L.); (J.M.S.)
| | - Elise Lemanski
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (B.M.G.); (N.A.H.); (E.L.); (J.M.S.)
| | - Ibrahim Malik
- Center for Biomedical and Brain Imaging, Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (I.M.); (K.H.)
| | - Khan Hekmatyar
- Center for Biomedical and Brain Imaging, Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (I.M.); (K.H.)
| | - Mark S. Parcells
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA;
| | - Jaclyn M. Schwarz
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, USA; (B.M.G.); (N.A.H.); (E.L.); (J.M.S.)
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Krstanović F, Britt WJ, Jonjić S, Brizić I. Cytomegalovirus Infection and Inflammation in Developing Brain. Viruses 2021; 13:1078. [PMID: 34200083 PMCID: PMC8227981 DOI: 10.3390/v13061078] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus that can cause severe disease in immunocompromised individuals and immunologically immature fetuses and newborns. Most infected newborns are able to resolve the infection without developing sequelae. However, in severe cases, congenital HCMV infection can result in life-threatening pathologies and permanent damage of organ systems that possess a low regenerative capacity. Despite the severity of the problem, HCMV infection of the central nervous system (CNS) remains inadequately characterized to date. Cytomegaloviruses (CMVs) show strict species specificity, limiting the use of HCMV in experimental animals. Infection following intraperitoneal administration of mouse cytomegalovirus (MCMV) into newborn mice efficiently recapitulates many aspects of congenital HCMV infection in CNS. Upon entering the CNS, CMV targets all resident brain cells, consequently leading to the development of widespread histopathology and inflammation. Effector functions from both resident cells and infiltrating immune cells efficiently resolve acute MCMV infection in the CNS. However, host-mediated inflammatory factors can also mediate the development of immunopathologies during CMV infection of the brain. Here, we provide an overview of the cytomegalovirus infection in the brain, local immune response to infection, and mechanisms leading to CNS sequelae.
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Affiliation(s)
- Fran Krstanović
- Center for Proteomics and Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (F.K.); (S.J.)
| | - William J. Britt
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Stipan Jonjić
- Center for Proteomics and Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (F.K.); (S.J.)
| | - Ilija Brizić
- Center for Proteomics and Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia; (F.K.); (S.J.)
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Lin K, Bieri G, Gontier G, Müller S, Smith LK, Snethlage CE, White CW, Maybury-Lewis SY, Villeda SA. MHC class I H2-Kb negatively regulates neural progenitor cell proliferation by inhibiting FGFR signaling. PLoS Biol 2021; 19:e3001311. [PMID: 34181639 PMCID: PMC8270425 DOI: 10.1371/journal.pbio.3001311] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 07/09/2021] [Accepted: 06/04/2021] [Indexed: 11/19/2022] Open
Abstract
Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.
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Affiliation(s)
- Karin Lin
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
- Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, United States of America
| | - Gregor Bieri
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
| | - Geraldine Gontier
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
| | - Sören Müller
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Lucas K. Smith
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, United States of America
| | - Cedric E. Snethlage
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
| | - Charles W. White
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
- Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, United States of America
| | - Sun Y. Maybury-Lewis
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, United States of America
| | - Saul A. Villeda
- Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America
- Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, United States of America
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, United States of America
- Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, United States of America
- Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, California, United States of America
- The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, United States of America
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Matejuk A, Vandenbark AA, Offner H. Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease. Front Neurol 2021; 12:672455. [PMID: 34135852 PMCID: PMC8200536 DOI: 10.3389/fneur.2021.672455] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
The immune system's role is much more than merely recognizing self vs. non-self and involves maintaining homeostasis and integrity of the organism starting from early development to ensure proper organ function later in life. Unlike other systems, the central nervous system (CNS) is separated from the peripheral immune machinery that, for decades, has been envisioned almost entirely as detrimental to the nervous system. New research changes this view and shows that blood-borne immune cells (both adaptive and innate) can provide homeostatic support to the CNS via neuroimmune communication. Neurodegeneration is mostly viewed through the lens of the resident brain immune populations with little attention to peripheral circulation. For example, cognition declines with impairment of peripheral adaptive immunity but not with the removal of microglia. Therapeutic failures of agents targeting the neuroinflammation framework (inhibiting immune response), especially in neurodegenerative disorders, call for a reconsideration of immune response contributions. It is crucial to understand cross-talk between the CNS and the immune system in health and disease to decipher neurodestructive and neuroprotective immune mechanisms for more efficient therapeutic strategies.
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Affiliation(s)
- Agata Matejuk
- Department of Immunology, Collegium Medicum, University of Zielona Góra, Zielona Góra, Poland
| | - Arthur A Vandenbark
- Neuroimmunology Research, VA Portland Health Care System, Portland, OR, United States.,Department of Neurology, Oregon Health and Science University, Portland, OR, United States.,Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, United States
| | - Halina Offner
- Neuroimmunology Research, VA Portland Health Care System, Portland, OR, United States.,Department of Neurology, Oregon Health and Science University, Portland, OR, United States.,Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, United States
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Matelski L, Morgan RK, Grodzki AC, Van de Water J, Lein PJ. Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line. Mol Psychiatry 2021; 26:875-887. [PMID: 31965031 PMCID: PMC7371517 DOI: 10.1038/s41380-020-0647-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 12/12/2019] [Accepted: 01/10/2020] [Indexed: 12/13/2022]
Abstract
Maternal infection during pregnancy is associated with increased risk of psychiatric and neurodevelopmental disorders (NDDs). Experimental animal models demonstrate that maternal immune activation (MIA) elevates inflammatory cytokine levels in the maternal and fetal compartments and causes behavioral changes in offspring. Individual cytokines have been shown to modulate neurite outgrowth and synaptic connectivity in cultured rodent neurons, but whether clinically relevant cytokine mixtures similarly modulate neurodevelopment in human neurons is not known. To address this, we quantified apoptosis, neurite outgrowth, and synapse number in the LUHMES human neuronal cell line exposed to varying concentrations of: (1) a mixture of 12 cytokines and chemokines (EMA) elevated in mid-gestational serum samples from mothers of children with autism and intellectual disability; (2) an inflammatory cytokine mixture (ICM) comprised of five cytokines elevated in experimental MIA models; or (3) individual cytokines in ICM. At concentrations that activated nuclear factor-kappa B (NF-κB) in LUHMES cells, EMA and ICM induced caspase-3/7 activity. ICM altered neurite outgrowth, but only at concentrations that also reduced cell viability, whereas ICM reduced synapse number independent of changes in cell viability. Individual cytokines in ICM phenocopied the effects of ICM on NF-κB activation and synaptic connectivity, but did not completely mimic the effects of ICM on apoptosis. These results demonstrate that clinically relevant cytokine mixtures modulate apoptosis and synaptic density in developing human neurons. Given the relevance of these neurodevelopmental processes in NDDs, our findings support the hypothesis that cytokines contribute to the adverse effects of MIA on children.
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Affiliation(s)
- Lauren Matelski
- Department of Internal Medicine, University of California, Davis,Department of Molecular Biosciences, University of California, Davis
| | - Rhianna K. Morgan
- Department of Molecular Biosciences, University of California, Davis
| | | | | | - Pamela J. Lein
- Department of Molecular Biosciences, University of California, Davis
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Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Bakheet SA, Alsanea S, Ali N, Albekairi TH, Alsaleh NB. Aggravation of autism-like behavior in BTBR T+tf/J mice by environmental pollutant, di-(2-ethylhexyl) phthalate: Role of nuclear factor erythroid 2-related factor 2 and oxidative enzymes in innate immune cells and cerebellum. Int Immunopharmacol 2021; 91:107323. [PMID: 33385713 DOI: 10.1016/j.intimp.2020.107323] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/04/2020] [Accepted: 12/16/2020] [Indexed: 12/17/2022]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which manifests itself in early childhood and is distinguished by recurring behavioral patterns, and dysfunction in social/communication skills. Ubiquitous environmental pollutant, di-2-ethylhexyl phthalate (DEHP) is one of the most frequently used plasticizers in various industrial products, e.g. vinyl flooring, plastic toys, and medical appliances. DEHP gets easily released into the environment and leads to human exposure through various routes. DEHP has been described to be linked with oxidative stress in various organs in animal/human studies. Increased concentration of DEHP has also been detected in ASD children which indicates an association between phthalates exposure and ASD. However, effect of DEHP on autism-like behavior has not been investigated previously. Therefore, this study probed the effect of DEHP on autism-like behavior (marble burying, self-grooming and sociability) and innate immune cells (dendritic cells/neutrophils)/cerebellar oxidant-antioxidant balance (NFkB, iNOS, NADPH oxidase, nitrotyrosine, lipid peroxides, Nrf2, SOD, GPx) in BTBR and C57 mice. Our data show that DEHP treatment causes worsening of autism-like behavior in BTBR mice which is associated with enhancement of oxidative stress in innate immune cells and cerebellum with concomitant lack of antioxidant protection. DEHP also causes oxidative stress in C57 mice in both innate immune cells and cerebellar compartment, however there is Nrf2-mediated induction of enzymatic antioxidants which protects them from upregulated oxidative stress. This proposes the notion that ubiquitous environmental pollutants such as DEHP may be involved in the pathogenesis/progression of ASD through dysregulation of antioxidant-antioxidant balance in innate immune cells and cerebellum.
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Affiliation(s)
- Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
| | - Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Naif O Al-Harbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Thamer H Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Nasser B Alsaleh
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Zein H, Mohammad K, Leijser LM, Brundler MA, Kirton A, Esser MJ. Cord Blood Cytokine Levels Correlate With Types of Placental Pathology in Extremely Preterm Infants. Front Pediatr 2021; 9:607684. [PMID: 33777861 PMCID: PMC7991101 DOI: 10.3389/fped.2021.607684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 02/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Placental abnormalities are associated with inflammation and have been linked to brain injury in preterm infants. We studied the relationship between placental pathology and the temporal profiles of cytokine levels in extremely pre-term infants. Study Design: We prospectively enrolled 55 extremely preterm infants born between June 2017 and July 2018. Levels of 27 cytokines were measured in blood drawn from the umbilical artery at birth and from infants at 1-3 and 21-28 days of life. Placental pathology was grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I). Results: Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin (p = 0.038), G-CSF (p = 0.023), IFN-γ (p = 0.002), IL-1ra (p < 0.001), IL-4 (p = 0.005), IL-8 (p = 0.010), MCP-1 (p = 0.011), and TNFα (p = 0.002). Post-hoc analysis revealed sex differences between and within the placental pathology groups. Conclusion: Specific types of placental pathology may be associated with differential cytokine profiles in extremely pre-term infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.
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Affiliation(s)
- Hussein Zein
- Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Khorshid Mohammad
- Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Lara M Leijser
- Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Marie-Anne Brundler
- Departments of Pathology and Laboratory Medicine and Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Adam Kirton
- Section of Pediatric Neurology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Michael J Esser
- Section of Pediatric Neurology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
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Esgalhado AJ, Reste-Ferreira D, Albino SE, Sousa A, Amaral AP, Martinho A, Oliveira IT, Verde I, Lourenço O, Fonseca AM, Cardoso EM, Arosa FA. CD45RA, CD8β, and IFNγ Are Potential Immune Biomarkers of Human Cognitive Function. Front Immunol 2020; 11:592656. [PMID: 33324408 PMCID: PMC7723833 DOI: 10.3389/fimmu.2020.592656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/12/2020] [Indexed: 11/23/2022] Open
Abstract
There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64–101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (Temrahi); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8βhi); (3) augmented production of IFNγ by in vitro activated CD4+ T cells. Noteworthy, CD3+CD8+ Temrahi and CD3+CD8βhi cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ Temra cells, and the amount of IFNγ produced by in vitro activated CD4+ T cells, with impaired cognitive function in the elderly.
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Affiliation(s)
- André J Esgalhado
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Débora Reste-Ferreira
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Stephanie E Albino
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Adriana Sousa
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Ana Paula Amaral
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - António Martinho
- Molecular Genetics Laboratory, Coimbra Blood and Transplantation Center, Coimbra, Portugal
| | - Isabel T Oliveira
- C4-UBI, Cloud Computing Competence Centre, University of Beira Interior, Covilhã, Portugal
| | - Ignacio Verde
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - Olga Lourenço
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - Ana M Fonseca
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - Elsa M Cardoso
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.,IPG, Guarda Polytechnic Institute, Guarda, Portugal
| | - Fernando A Arosa
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
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Wulaer B, Hada K, Sobue A, Itoh N, Nabeshima T, Nagai T, Yamada K. Overexpression of astroglial major histocompatibility complex class I in the medial prefrontal cortex impairs visual discrimination learning in mice. Mol Brain 2020; 13:170. [PMID: 33317605 PMCID: PMC7734728 DOI: 10.1186/s13041-020-00710-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/02/2020] [Indexed: 01/12/2023] Open
Abstract
Background Immune molecules, such as cytokines, complement, and major histocompatibility complex (MHC) proteins, in the central nervous system are often associated with neuropsychiatric disorders. Neuronal MHC class I (MHCI), such as H-2D, regulate neurite outgrowth, the establishment and function of cortical connections, and activity-dependent refinement in mice. We previously established mice expressing MHCI specifically in astrocytes of the media prefrontal cortex (mPFC) using the adeno-associated virus (AAV) vector under the control of the GfaABC1D promoter. Mice expressing the soluble form of H-2D (sH-2D) in the mPFC (sH-2D-expressing mice) showed abnormal behaviors, including social interaction deficits and cognitive dysfunctions. However, the pathophysiological significance of astroglial MHCI on higher brain functions, such as learning, memory, and behavioral flexibility, remains unclear. Therefore, cognitive function in mice expressing sH-2D in astrocytes of the mPFC was tested using the visual discrimination (VD) task. Methods sH-2D-expressing mice were subjected to the VD and reversal learning tasks, and morphological analysis. Results In the pretraining, sH-2D-expressing mice required significantly more trials to reach the learning criterion than control mice. The total number of sessions, trials, normal trials, and correction trials to reach the VD criterion were also significantly higher in sH-2D-expressing mice than in control mice. A morphological study showed that dendritic complexity and spine density were significantly reduced in the dorsal striatum of sH-2D-expressing mice. Conclusion Collectively, the present results suggest that the overexpression of astroglial MHCI in the mPFC results in impaired VD learning, which may be accompanied by decreased dendritic complexity in the dorsal striatum and mPFC.
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Affiliation(s)
- Bolati Wulaer
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.,Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, 470-1192, Japan
| | - Kazuhiro Hada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Akira Sobue
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Norimichi Itoh
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, 470-1192, Japan
| | - Taku Nagai
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
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50
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Ijomone OM, Olung NF, Akingbade GT, Okoh COA, Aschner M. Environmental influence on neurodevelopmental disorders: Potential association of heavy metal exposure and autism. J Trace Elem Med Biol 2020; 62:126638. [PMID: 32891009 PMCID: PMC7655547 DOI: 10.1016/j.jtemb.2020.126638] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Environmental factors have been severally established to play major roles in the pathogenesis of neurodevelopmental disorders including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that is associated with symptoms that reduce the quality of life of affected individuals such as social interaction deficit, cognitive impairment, intellectual disabilities, restricted and repetitive behavioural patterns. ASD pathogenesis has been associated with environmental and genetic factors that alter physiologic processes during development. Here, we review literatures highlighting the environmental impact on neurodevelopmental disorders, and mechanisms by which environmental toxins may influence neurodevelopment. Furthermore, this review discusses reports highlighting neurotoxic metals (specifically, lead, mercury, cadmium, nickel and manganese) as environmental risk factors in the aetiology of ASD. This work, thus suggests that improving the environment could be vital in the management of ASD.
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Affiliation(s)
- Omamuyovwi M Ijomone
- The Neuro- Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria; Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria.
| | - Nzube F Olung
- The Neuro- Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Grace T Akingbade
- The Neuro- Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria; Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Comfort O A Okoh
- The Neuro- Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, NY, USA; IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
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