Related Experiment Video
Updated: Apr 26, 2026
Hypoxia Alters miRNAs Levels Involved in Non-Mendelian Inheritance of Autism Spectrum Disorder in Mice
Published on: July 11, 2025
Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain
Lauren L Jantzie, Christopher J Corbett, Jacqueline Berglass
1Departments of Neurology and Neurosurgery, F,M, Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Shenandoah.Robinson@childrens.harvard.edu.
Insights
Hypoxia-ischemia (HI) and inflammation in preterm infants cause distinct white matter and axonal injuries, leading to significant gait deficits. Understanding these differences is crucial for developing targeted therapies for preterm brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Preterm infants often experience combined hypoxia-ischemia (HI) and perinatal inflammation, leading to severe neurodevelopmental issues like cerebral palsy and epilepsy.
- A novel rat model simulating late-gestation HI and lipopolysaccharide (LPS)-induced inflammation was used to investigate differential injury patterns.
Purpose of the Study:
- To test the hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development, and motor impairment in the first postnatal month.
- To elucidate the distinct injury mechanisms and long-term consequences of combined HI and inflammatory insults in a preterm model.
Main Methods:
- Pregnant rats received transient systemic HI (TSHI) and/or intra-amniotic LPS injection on embryonic day 18.
- Immunohistochemistry, Western blots, quantitative PCR, and Digigait analysis were employed to assess glial response, myelin basic protein and neurofilament expression, erythropoietin levels, and gait deficits.
- Statistical analysis included one-way ANOVA with Bonferroni correction.
Main Results:
- Combined TSHI + LPS elevated microglial and astroglial responses early on, with reduced myelin basic protein at postnatal day 15.
- TSHI alone induced chronic white matter and axonal injury by postnatal day 28, evidenced by reduced myelin basic protein and phosphoneurofilament/neurofilament ratio.
- All injury groups exhibited significant ataxic gait deficits, impacting stride, paw placement, and coordination.
Conclusions:
- Prenatal TSHI and combined TSHI + LPS induce distinct patterns of white matter, axonal, and gait injuries.
- Dual insults cause acute inflammatory changes, while TSHI alone leads to more pronounced chronic white matter and axonal damage.
- These findings aid in stratifying injury mechanisms in preterm infants and guiding therapeutic interventions.
Background:
Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month.
Methods:
Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction.
Results:
Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).
Conclusions:
Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.
Related Concept Videos
01:07Teratogenicity
01:22Gut-Brain Axis