Abstract
Systemic hypoxia-ischemia (HI) often occurs during preterm birth in human. HI induces injuries to hinder brain cells mainly in the ipsilateral forebrain structures. Such HI injuries may cause lifelong disturbances in the distant regions, such as the contralateral side of the cerebellum. We aimed to evaluate behavior associated with the cerebellum, to acquire cerebellar abundant metabolic alterations using in vivo 1H magnetic resonance spectroscopy (1H MRS), and to determine GFAP, NeuN, and MBP protein expression in the left cerebellum, in adult rats after mild early postnatal HI on the right forebrain at day 3 (PND3). From PND45, HI animals exhibited increased locomotion in the open field while there is neither asymmetrical forelimb use nor coordination deficits in the motor tasks. Despite the fact that metabolic differences between two cerebellar hemispheres were noticeable, a global increase in glutamine of HI rats was observed and became significant in the left cerebellum compared to the sham-operated group. Furthermore, increases in glutamate, glycine, the sum of glutamate and glutamine and total choline, only occurred in the left cerebellum of HI rats. Remarkably, there were decreased expression of MBP and NeuN but no detectable reactive astrogliosis in the contralateral side of the cerebellum of HI rats. Taken together, the detected alterations observed in the left cerebellum of HI rats may reflect disequilibrium in the glutamate-glutamine cycle and a delay in the return of glutamine from astrocytes to neurons from hypoxic-ischemic origin. Our data provides in vivo evidence of long-term changes in the corresponding cerebellum following mild neonatal HI in very immature rats, supporting the notion that systemic HI could cause cell death in the cerebellum, a distant region from the expected injury site.HIGHLIGHTS-Neonatal hypoxia-ischemia (HI) in very immature rats induces hyperactivity toward adulthood.-1H magnetic resonance spectroscopy detects long-term cerebellar metabolic changes in adult rats after neonatal HI at postnatal day 3.-Substantial decreases of expression of neuronal and myelin markers in adult rats cerebellum after neonatal cortical mild HI.
Highlights
Complications derived from premature birth account for 29% of global neonatal deaths yearly and around 3% of total disability during the lifespan (Lawn et al, 2010; Howson et al, 2013)
We aimed to evaluate behavior associated with the cerebellum, to acquire cerebellar abundant metabolic alterations using in vivo 1H magnetic resonance spectroscopy (1H MRS), and to determine GFAP, NeuN, and myelin basic protein (MBP) protein expression in the left cerebellum, in adult rats after mild early postnatal HI on the right forebrain at day 3 (PND3)
Studies using HI at postnatal day 7 have shown that cell death occurs in brain regions that are not directly affected by ischemia, such as the cerebellum (Joyal et al, 1996; Kim et al, 2004; Northington et al, 2011) suggesting that neuronal connectivity may play a role in neurodegeneration following HI to the immature brain
Summary
Complications derived from premature birth account for 29% of global neonatal deaths yearly and around 3% of total disability during the lifespan (Lawn et al, 2010; Howson et al, 2013). Since cerebellum has a major role in high order brain functions, lesions in its connections with cortical and sub-cortical centers could lead to motor and verbal impairments (Marr, 1969; Barradas et al, 2016) and to cognitive, affective and social disturbances (Schmahmann et al, 2008; Limperopoulos et al, 2009; Kitai et al, 2015). Pathologic evidence of cerebellar injury in neonates has gained valuable input with the advances in numerous magnetic resonance imaging (MRI) techniques (reviewed by Smyser et al, 2018) in which many HI injury characteristics (Schneider et al, 2009; Matsufuji et al, 2017) and other early-life cerebellar impairments associated with brain injury in premature infants can be detected (Limperopoulos, 2005a,b). 1H MRS shows early alterations in brain structure and metabolism highly correlated to HI in clinical and preclinical settings (Roelants-Van Rijn et al, 2001; van de Looij et al, 2015; Xu et al, 2015) and could be used as a biomarker for late-term neurodevelopmental outcomes following HI
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