Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity

Ohshima, Makiko; Coq, Jacques‐Olivier; Otani, Kentaro; Hattori, Yorito; Ogawa, Yuko; Sato, Yoshiaki; Harada‐Shiba, Mariko; Ihara, Masafumi; Tsuji, Masahiro

doi:10.1038/srep39377

Cited by 31 publications

(58 citation statements)

References 46 publications

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“…In contrast to these results, the nucleus accumbens showed no significant differences in size among groups, though Olig2+ cell counts were lower in both IUGR groups. Interestingly, even in a model of “mild intrauterine hypo-perfusion”, neurological development impairment is observed, with reduced white and gray matter areas despite evident tissue injury [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents

et al. 2017

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BackgroundCerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits.MethodsEffects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests.ResultsNeuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions.ConclusionsWe have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.

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Section: Discussionmentioning

confidence: 99%

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents

et al. 2017

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“…The muscle strength of the limbs was assessed by a traction meter with steel grids (Brain Science Idea, Co., Limited, Osaka, Japan) at 10 weeks of age as described previously with minor modifications (Ohshima et al, 2016). The four limbs of each mouse were placed on the steel grid of the apparatus, and an experimenter slowly pulled the tail backward and parallel to the surface of the grid at a constant speed.…”

Section: Traction Metermentioning

confidence: 99%

Cilostazol, a Phosphodiesterase 3 Inhibitor, Moderately Attenuates Behaviors Depending on Sex in the Ts65Dn Mouse Model of Down Syndrome

Tsuji

Ohshima

Yamamoto

et al. 2020

Front. Aging Neurosci.

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People with Down syndrome, which is a trisomy of chromosome 21, exhibit intellectual disability from infancy and neuropathology similar to Alzheimer's disease, such as amyloid plaques, from an early age. Recently, we showed that cilostazol, a selective inhibitor of phosphodiesterase (PDE) 3, promotes the clearance of amyloid β and rescues cognitive deficits in a mouse model of Alzheimer's disease. The objective of the present study was to examine whether cilostazol improves behaviors in the most widely used animal model of Down syndrome, i.e., Ts65Dn mice. Mice were supplemented with cilostazol from the fetal period until young adulthood. Supplementation significantly ameliorated novel-object recognition in Ts65Dn females and partially ameliorated sensorimotor function as determined by the rotarod test in Ts65Dn females and hyperactive locomotion in Ts65Dn males. Cilostazol supplementation significantly shortened swimming distance in Ts65Dn males in the Morris water maze test, suggesting that the drug improved cognitive function, although it did not shorten swimming duration, which was due to decreased swimming speed. Thus, this study suggests that early supplementation with cilostazol partially rescues behavioral abnormalities seen in Down syndrome and indicates that the effects are sex-dependent.

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“…With increasing prevalence, encephalopathy of prematurity (EP) is mainly characterized by gray matter dysmaturation and reduction, diffuse white matter injury (WMI) related to abnormal oligodendroglial precursor maturation leading to hypomyelination, minor to mild sensorimotor, behavioral and cognitive disorders, and often results in CP ( 1 ). Although the relations between the NDDs, brain damage, perinatal hypoxia-ischemia, and neuroinflammation are not completely clear and understood ( 3 , 5 ), we recently developed a rodent model of EP, based on prenatal ischemia ( 6 ) which in fact better corresponds to mild intrauterine hypoperfusion (MIUH) ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Mild Intrauterine Hypoperfusion Leads to Lumbar and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats: Implications for Prematurity

et al. 2018

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Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.

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Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity

Cited by 31 publications

References 46 publications

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents

Cilostazol, a Phosphodiesterase 3 Inhibitor, Moderately Attenuates Behaviors Depending on Sex in the Ts65Dn Mouse Model of Down Syndrome

Mild Intrauterine Hypoperfusion Leads to Lumbar and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats: Implications for Prematurity

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