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      Recent insights from non-mammalian models of brain injuries: an emerging literature


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          Traumatic brain injury (TBI) is a major global health concern and is increasingly recognized as a risk factor for neurodegenerative diseases including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Repetitive TBIs (rTBIs), commonly observed in contact sports, military service, and intimate partner violence (IPV), pose a significant risk for long-term sequelae. To study the long-term consequences of TBI and rTBI, researchers have typically used mammalian models to recapitulate brain injury and neurodegenerative phenotypes. However, there are several limitations to these models, including: (1) lengthy observation periods, (2) high cost, (3) difficult genetic manipulations, and (4) ethical concerns regarding prolonged and repeated injury of a large number of mammals. Aquatic vertebrate model organisms, including Petromyzon marinus (sea lampreys), zebrafish ( Danio rerio), and invertebrates, Caenorhabditis elegans ( C. elegans), and Drosophila melanogaster ( Drosophila), are emerging as valuable tools for investigating the mechanisms of rTBI and tauopathy. These non-mammalian models offer unique advantages, including genetic tractability, simpler nervous systems, cost-effectiveness, and quick discovery-based approaches and high-throughput screens for therapeutics, which facilitate the study of rTBI-induced neurodegeneration and tau-related pathology. Here, we explore the use of non-vertebrate and aquatic vertebrate models to study TBI and neurodegeneration. Drosophila, in particular, provides an opportunity to explore the longitudinal effects of mild rTBI and its impact on endogenous tau, thereby offering valuable insights into the complex interplay between rTBI, tauopathy, and neurodegeneration. These models provide a platform for mechanistic studies and therapeutic interventions, ultimately advancing our understanding of the long-term consequences associated with rTBI and potential avenues for intervention.

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          Most cited references147

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          The blood-brain barrier.

          Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
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            Estimating the global incidence of traumatic brain injury

            Traumatic brain injury (TBI)—the “silent epidemic”—contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. Open-source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64–74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650–1947) and Europe (1012 cases, 95% CI 911–1113) and least in Africa (801 cases, 95% CI 732–871) and the Eastern Mediterranean (897 cases, 95% CI 771–1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. Sixty-nine million (95% CI 64–74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe.
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              Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research


                Author and article information

                URI : https://loop.frontiersin.org/people/2635233/overviewRole: Role: Role: Role: Role: Role:
                Role: Role: Role: Role: Role: Role:
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                19 March 2024
                : 15
                : 1378620
                [1] 1Department of Molecular Biology, Princeton University , Princeton, NJ, United States
                [2] 2Rutgers-Robert Wood Johnson Medical School , Piscataway, NJ, United States
                Author notes

                Edited by: Fawaz Alzaid, Sorbonne Universités, France

                Reviewed by: Jacek Szczygielski, University of Rzeszow, Poland

                Jonathan D. Cherry, Boston University, United States

                *Correspondence: Nicole J. Katchur, nkatchur@ 123456princeton.edu
                Copyright © 2024 Katchur and Notterman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 29 January 2024
                : 26 February 2024
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 148, Pages: 11, Words: 11097
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This publication was supported by the New Jersey Commission on Brain Injury Research CBIR23FEL005, the Center of Health and Well-being at Princeton University, the Brain Injury Association of America, and the Princeton Library Open Access Fund.
                Custom metadata

                repetitive brain injury,non-mammalian models,neurodegeneration,tauopathy,traumatic brain injury


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