Knowledge Gaps and Emerging Research Areas in Intrauterine Growth Restriction-Associated Brain Injury

Fleiss, Bobbi; Wong, Flora Y.; Brownfoot, Fiona; Shearer, Isabelle K; Baud, Olivier; Walker, David W.; Gressèns, Pierre; Tolcos, Mary

doi:10.3389/fendo.2019.00188

Cited by 49 publications

(53 citation statements)

References 262 publications

(275 reference statements)

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“…Additionally, a model of intrauterine growth restriction in pig, initiated at 100 days of pregnancy and assessed 22 days later, showed a loss of MAP2 staining in the parietal cortex and hippocampus, which was interpreted as disrupted somatodendritic neurites (162). Intrauterine growth restriction is an important contributor to poor perinatal outcomes, particularity in preterm born infants [see (163)]. Reduced dendritic branching and spine immaturity have also been reported in the CA1 region of hippocampus in a model of preterm birth in rabbit kits (30) and in the granular layer of the dentate gyrus in a maternal inflammatory activation (using i.p.…”

Section: Eop As a Synaptopathymentioning

confidence: 99%

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice.

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Section: Eop As a Synaptopathymentioning

confidence: 99%

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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“…[6][7][8][9] Different animal models and advanced imaging techniques have been used to better understand the mechanisms underlying neuronal impairments and perinatal brain maturation alterations induced by IUGR. 10 However, there is still a large knowledge gap on the mechanisms underlying these alterations 2 and a lack of research models to better characterize the IUGR-associated brain injury (reviewed by Fleiss et al 2019 11 ).…”

Section: Introductionmentioning

confidence: 99%

Rabbit neurospheres as a novel in vitro tool for studying neurodevelopmental effects induced by intrauterine growth restriction

Barenys

Illa

Hofrichter

et al. 2020

Stem Cells Translational Medicine

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The aim of this study was to develop a rabbit neurosphere culture to characterize differences in basic processes of neurogenesis induced by intrauterine growth restriction (IUGR). A novel in vitro neurosphere culture has been established using fresh or frozen neural progenitor cells from newborn (PND0) rabbit brains. After surgical IUGR induction in pregnant rabbits and cesarean section 5 days later, neural progenitor cells from both control and IUGR groups were isolated and directly cultured or frozen at −80 C. These neural progenitor cells spontaneously formed neurospheres after 7 days in culture. The ability of control and IUGR neurospheres to migrate, proliferate, differentiate to neurons, astrocytes, or oligodendrocytes was compared and the possibility to modulate their responses was tested by exposure to several positive and negative controls. Neurospheres obtained from IUGR brains have a significant impairment in oligodendrocyte differentiation, whereas no significant differences are observed in other basic processes of neurogenesis. This impairment can be reverted by in vitro exposure of IUGR neurospheres to thyroid hormone, which is known to play an essential role in white matter maturation in vivo. Our new rabbit neurosphere model and the results of this study open the possibility to test several substances in vitro as neuroprotective candidates against IUGR induced neurodevelopmental damage while decreasing the number of animals and resources and allowing a more mechanistic approach at a cellular functional level.

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“…inflammation, identified to activate microglia (3), the resident macrophages of the central nervous system (CNS), and to be the best predictor of subsequent neurological impairment (4,5). Microglial cells can acquire distinct phenotypes in response to perinatal stimuli that allow them to not only disrupt developmental processes but also support repair and regeneration.…”

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confidence: 99%

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

Zinni

Mairesse

Pansiot

et al. 2020

Preprint

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Background: Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence support a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia.Methods: We used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular approaches.Results: Exposure to LPD/IL-1β significantly down-regulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central position in the control of inflammation in resting and activated microglia. Microglia hyper-reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade and siRNA knock-down of mGlu3 receptors in control microglia mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β.Conclusions: Overall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.

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Knowledge Gaps and Emerging Research Areas in Intrauterine Growth Restriction-Associated Brain Injury

Cited by 49 publications

References 262 publications

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Rabbit neurospheres as a novel in vitro tool for studying neurodevelopmental effects induced by intrauterine growth restriction

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

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