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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell
Sterling B Ortega1, Xiagmei Kong1, Ramgopal Venkataraman1
1Departments of *Neurology and Neurotherapeutics and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Departments of Pediatrics and Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA; and Department of Accounting, School of Business, University of Texas at Arlington, Arlington, Texas, USA.
Insights
Perinatal hypoxia-ischemia (pCH) impairs brain development by reducing mature myelin and increasing autoreactive T cells. This leads to long-term motor deficits and hypomyelination in developing brains.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Perinatal hypoxia-ischemia (pCH) is a significant risk factor for pediatric brain injury and long-term neurological deficits.
- Brain development involves critical stages like neurogenesis, neuronal migration, and myelination, which are vulnerable to insults like pCH.
Purpose of the Study:
- To investigate the impact of a rodent model of pCH on myelin development and neuroinflammation.
- To explore the role of oligodendrocyte progenitor cells and T cell infiltration in pCH-induced brain injury.
Main Methods:
- Utilized a rodent model to induce perinatal hypoxia-ischemia (pCH).
- Assessed myelin levels and oligodendrocyte progenitor cell proliferation using BrdU labeling.
- Quantified CD4 T cell infiltration and myelin-specific T cells in the developing brain.
Main Results:
- pCH led to early decreases in mature myelin and impaired myelinogenesis due to reduced oligodendrocyte progenitor cell division.
- Mice exhibited persistent hypomyelination and long-term motor function deficits after pCH cessation.
- pCH induced neuroinflammation, characterized by increased CD4 T cell infiltration and oligodendrocyte-directed autoimmunity.
Conclusions:
- Both the depletion of mature myelin-producing cells and T cell-mediated autoimmunity contribute to pCH-induced hypomyelination.
- Understanding hypoxia-driven autoimmunity is crucial for addressing the neuroimmune axis in perinatal CNS diseases.
- These findings highlight potential mechanisms for long-term functional disability following perinatal brain injury.
Abstract:
pCH is an important risk factor for brain injury and long-term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long-term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH-mediated neuroinflammation included oligodendrocyte-directed autoimmunity, with an increase in peripheral myelin-specific CD4 T cells. Thus, both the loss of available, mature, myelin-producing glial cells and an active increase in autoreactive, myelin-specific CD4 T cell infiltration into pCH brains may contribute to early pCH-induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia-driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long-term functional disability.
