Diversifying and Strengthening Translational Animal Models of Newborn Brain Injuries

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 9650

Special Issue Editors


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Guest Editor
1. Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
2. Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA
Interests: neonatal; hypoxia–ischemia; neurology; neuroprotection; inflammation

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Guest Editor
Neonatology and Pediatric Intensive Care, University of Bonn, School of Medicine, University Hospital Bonn, 53127 Bonn, Germany
Interests: neonatal; hypoxia–ischemia; neurology; neuroprotection; inflammation

Special Issue Information

Dear Colleagues,

We hope that you are well! We are reaching out to you with an invitation to contribute to a special edition of Life entitled “Diversifying and Strengthening Translational Animal Models of Newborn Brain Injuries”.

The developmental brain injury field is unique within the arena of translational neuroscience, as it has a well-defined and successful pipeline of preclinical models with which to understand the mechanisms of newborn brain injury and develop potential neurotherapeutics. However, while this is particularly true for acute term hypoxic–ischemic (HI) brain injury, preclinical models of premature brain injury and other pathological causes of, or risk factors for, neonatal brain injury such as intracerebral hemorrhage, environmental exposures, neonatal stroke, and genetic mutations, have yet to show robust clinical translation. At the same time, the field has not routinely controlled for critical variables in preclinical rodent models that can affect internal and external validity; better assessments of sex effects, the use of group sizes large enough to account for model variability, and the control of temperature as a critical confounder when assessing neuroprotection are required. This special edition of Life welcomes attempts to address these gaps. In particular, we hope to include primary research that 1) expands and diversifies the preclinical pipeline of animal models in newborn brain injury, 2) brings promising therapeutics closer to translation through more clinically relevant or better-controlled experiments, and 3) provides methods that can increase the external validity of rodent models of brain injury. Notable negative results and the rigorous repetition of other work is also welcomed.

We hope that you will consider contributing to this special edition and look forward to working with you!

Dr. Thomas R. Wood
Dr. Hemmen Sabir
Guest Editors

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Keywords

  • neonatal
  • hypoxia–ischemia
  • neurology
  • neuroprotection
  • inflammation
  • preclinical
  • prematurity
  • animal model

Published Papers (5 papers)

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Research

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9 pages, 1095 KiB  
Communication
Pilot Translational Precision Biobehavioral Assays for Early Detection of Motor Impairments in a Rat Model of Cerebral Palsy
by Gwendolyn Gerner, Vera Joanna Burton, Yuma Kitase, Shenandoah Robinson and Lauren L. Jantzie
Life 2023, 13(8), 1746; https://doi.org/10.3390/life13081746 - 14 Aug 2023
Viewed by 892
Abstract
Background: Cutting-edge neonatal programs diagnose cerebral palsy (CP) or “high risk of CP” using validated neurobehavioral exams in combination with risk history and neuroimaging. In rat models, digital gait analyses are the gold standard adult assessment, but tools in infant rats are limited. [...] Read more.
Background: Cutting-edge neonatal programs diagnose cerebral palsy (CP) or “high risk of CP” using validated neurobehavioral exams in combination with risk history and neuroimaging. In rat models, digital gait analyses are the gold standard adult assessment, but tools in infant rats are limited. Refinement of infant rat neurobehavioral correlates of CP will establish translational behavioral biomarkers to delineate early mechanisms of CP in both humans and rodent models of CP. Objective: To facilitate precision medicine approaches of neurodevelopmental health and integrate basic and clinical research approaches for CP, we developed and piloted a new assay of neonatal rat neurobehavior to mimic human neonate exams. Methods: Our established rat model of CP secondary to chorioamnionitis (CHORIO) that induces bilateral motor impairment reminiscent of spastic CP was used. On postnatal day 10 (P10), 5 min videos were recorded of 26 (6 sham and 20 CHORIO) animals moving freely in a cage were reviewed by an evaluator trained in the human General Movements Assessment (GMA). Non-blinded observation revealed two behaviors that differed between rat pups in each group (time spent rearing; multi-dimensional nose sweeping; and sniffing). Each video was re-coded for these criteria by an evaluator blind to group status. Differences between sham and CP groups were analyzed using a Mann–Whitney U-test or Student’s t-test (p < 0.05 level of significance). Results: Neonatal rats with CP exhibited sensorimotor impairment and decreased spatial exploration. CP rats spent significantly less time rearing (17.85 ± 1.60 s vs. 34.8 ± 2.89 s, p = 0.007) and engaged in multi-dimensional nose sweeping and sniffing (2.2 ± 0.58 episodes vs. 5.5 ± 0.96 episodes, p = 0.03) than sham controls. Conclusions: These pilot findings of harmonized translational and precision biobehavioral assays provide an opportunity for increased expediency of clinical trials at the earliest stages of brain development. Full article
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24 pages, 14608 KiB  
Article
Unbiased Quantitative Single-Cell Morphometric Analysis to Identify Microglia Reactivity in Developmental Brain Injury
by Mark St. Pierre, Sarah Ann Duck, Michelle Nazareth, Camille Fung, Lauren L. Jantzie and Raul Chavez-Valdez
Life 2023, 13(4), 899; https://doi.org/10.3390/life13040899 - 28 Mar 2023
Cited by 1 | Viewed by 1895
Abstract
Microglia morphological studies have been limited to the process of reviewing the most common characteristics of a group of cells to conclude the likelihood of a “pathological” milieu. We have developed an Imaris-software-based analytical pipeline to address selection and operator biases, enabling use [...] Read more.
Microglia morphological studies have been limited to the process of reviewing the most common characteristics of a group of cells to conclude the likelihood of a “pathological” milieu. We have developed an Imaris-software-based analytical pipeline to address selection and operator biases, enabling use of highly reproducible machine-learning algorithms to quantify at single-cell resolution differences between groups. We hypothesized that this analytical pipeline improved our ability to detect subtle yet important differences between groups. Thus, we studied the temporal changes in Iba1+ microglia-like cell (MCL) populations in the CA1 between P10–P11 and P18–P19 in response to intrauterine growth restriction (IUGR) at E12.5 in mice, chorioamnionitis (chorio) at E18 in rats and neonatal hypoxia–ischemia (HI) at P10 in mice. Sholl and convex hull analyses differentiate stages of maturation of Iba1+ MLCs. At P10–P11, IUGR or HI MLCs were more prominently ‘ameboid’, while chorio MLCs were hyper-ramified compared to sham. At P18–P19, HI MLCs remained persistently ‘ameboid’ to ‘transitional’. Thus, we conclude that this unbiased analytical pipeline, which can be adjusted to other brain cells (i.e., astrocytes), improves sensitivity to detect previously elusive morphological changes known to promote specific inflammatory milieu and lead to worse outcomes and therapeutic responses. Full article
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21 pages, 4256 KiB  
Article
Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome
by Victoria Dahl, Hawley Helmbrecht, Ana Rios Sigler, Kate Hildahl, Holly Sullivan, Sanjana Janakiraman, Saahiti Jasti and Elizabeth Nance
Life 2022, 12(9), 1308; https://doi.org/10.3390/life12091308 - 25 Aug 2022
Cited by 1 | Viewed by 2010
Abstract
The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and [...] Read more.
The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions—the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs. Full article
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17 pages, 4461 KiB  
Article
Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild–Moderate Neonatal Hypoxia-Ischemia Brain Injury Model
by Anne Ehlting, Margit Zweyer, Elke Maes, Yvonne Schleehuber, Hardik Doshi, Hemmen Sabir and Maria Eugenia Bernis
Life 2022, 12(8), 1164; https://doi.org/10.3390/life12081164 - 30 Jul 2022
Cited by 5 | Viewed by 2314
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in [...] Read more.
Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3–10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate–severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild–moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild–moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild–moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild–moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild–moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question. Full article
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Review

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16 pages, 1264 KiB  
Review
Therapeutic Interventions in Rat Models of Preterm Hypoxic Ischemic Injury: Effects of Hypothermia, Caffeine, and the Influence of Sex
by Ruth McLeod, Ted Rosenkrantz and Roslyn Holly Fitch
Life 2022, 12(10), 1514; https://doi.org/10.3390/life12101514 - 28 Sep 2022
Cited by 7 | Viewed by 1561
Abstract
Infants born prematurely have an increased risk of experiencing brain injury, specifically injury caused by Hypoxia Ischemia (HI). There is no approved treatment for preterm infants, in contrast to term infants that experience Hypoxic Ischemic Encephalopathy (HIE) and can be treated with hypothermia. [...] Read more.
Infants born prematurely have an increased risk of experiencing brain injury, specifically injury caused by Hypoxia Ischemia (HI). There is no approved treatment for preterm infants, in contrast to term infants that experience Hypoxic Ischemic Encephalopathy (HIE) and can be treated with hypothermia. Given this increased risk and lack of approved treatment, it is imperative to explore and model potential treatments in animal models of preterm injury. Hypothermia is one potential treatment, though cooling to current clinical standards has been found to be detrimental for preterm infants. However, mild hypothermia may prove useful. Caffeine is another treatment that is already used in preterm infants to treat apnea of prematurity, and has shown neuroprotective effects. Both of these treatments show sex differences in behavioral outcomes and neuroprotective effects, which are critical to explore when working to translate from animal to human. The effects and research history of hypothermia, caffeine and how sex affects these treatment outcomes will be explored further in this review article. Full article
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