Patterns of Cerebral Injury in a Primate Model of Preterm Birth and Neonatal Intensive Care
ABSTRACT Very preterm birth is associated with significant neurodevelopmental morbidity, with 10% to 15% of these infants later developing cerebral palsy and up to 50% experiencing learning disabilities. The nature of the cerebral lesion predisposing these infants to such impairments is not fully understood but is likely related to both cerebral injury and alterations in cerebral development associated with neonatal intensive care. To study the impact of both preterm birth and neonatal intensive care on the immature brain, we are studying a preterm primate model delivered at 125 days of a 184-day gestational period and cared for in a neonatal intensive care unit for 2 to 4 weeks in a fashion highly similar to that for human preterm infants. The most common neuropathology in this model is white-matter damage manifested by reactive astrogliosis or activated microglia and enlarged ventricular size. Subarachnoid, germinal matrix, and intraventricular hemorrhages are also common. These preliminary results support the similarity of this model to both the alterations in cerebral developmental and the pattern of cerebral injury found in human preterm infants. We are now investigating the impact of randomized respiratory therapies on the pattern of cerebral injury. The prematurely born baboon appears to be an accurate and relevant model for the study of preterm human birth.
- SourceAvailable from: Regina Vontell
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- "Despite advances in neonatal care, there is still significant mortality and morbidity arising from injuries to the developing brain following preterm delivery. Preterm infants have high rates of injury to white matter structures and subsequent reduced volume of grey matter structures [16,17,18]. "
ABSTRACT: Toll-like receptors (TLRs) are members of the pattern recognition receptor family that detect components of foreign pathogens or endogenous molecules released in response to injury. Recent studies demonstrate that TLRs also have a functional role in regulating neuronal proliferation in the developing brain. This study investigated cellular expression of TLR3 using immunohistochemistry on human brain tissue. The tissue sections analysed contained anterior and lateral periventricular white matter from the frontal and parietal lobes in post-mortem neonatal cases with a postmenstrual age range of 23.6-31.4 weeks. In addition to preterm brains without overt pathology (control), preterm pathology cases with evidence of white matter injuries (WMI) were also examined. In order to identify TLR-positive cells, we utilized standard double-labelling immunofluorescence co-labelling techniques and confocal microscopy to compare co-expression of TLR3 with a neuronal marker (NeuN) or with glial markers (GFAP for astrocytes, Iba-1 for microglia and Olig2 for oligodendrocytes). We observed an increase in the neuronal (28 vs. 17%) and astroglial (38 vs. 21%) populations in the WMI group compared to controls in the anterior regions of the periventricular white matter in the frontal lobe. The increase in neurons and astrocytes in the WMI cases was associated with an increase in TLR3 immunoreactivity. This expression was significantly increased in the astroglia. The morphology of the TLR3 signal in the control cases was globular and restricted to the perinuclear region of the neurons and astrocytes, whilst in the cases of WMI, both neuronal, axonal and astroglial TLR3 expression was more diffuse (i.e., a different intracellular distribution) and could be detected along the extensions of the processes. This study demonstrates for the first time that neurons and glial cells in human neonatal periventricular white matter express TLR3 during development. The patterns of TLR3 expression were altered in the presence of WMI, which might influence normal developmental processes within the immature brain. Identifying changes in TLR3 expression during fetal development may be key to understanding the reduced volumes of grey matter and impaired cortical development seen in preterm infants.Developmental Neuroscience 03/2013; 35(2-3). DOI:10.1159/000346158 · 2.45 Impact Factor
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- "Moreover, long-term follow up in children with acquired brain injury suggests that even those with apparently normal or good outcomes sustain deficits in neurologic performance compared to their peers (Robertson et al., 2002). The hippocampus is frequently injured after hypoxic-ischemic brain injury and contains a discrete population of neural stem and progenitor cells (NSPs) that produce new granular cell neurons throughout life (Altman and Das, 1965; Cameron and McKay, 2001; Inder et al., 2005; Kinney et al., 2005). Although the functional significance of hippocampal neurogenesis remains unclear, there is tremendous speculation regarding how neural progenitors may mediate brain repair and subsequent recovery following injury (Kruger and Morrison, 2002; Emsley et al., 2005). "
ABSTRACT: Although the phenomenon of ongoing neurogenesis in the hippocampus is well described, it remains unclear what relevance this has in terms of brain self-repair following injury. In a highly regulated developmental program, new neurons are added to the inner granular cell layer of the dentate gyrus (DG) where slowly dividing radial glial-like type 1 neural stem/progenitors (NSPs) give rise to rapidly proliferating type 2 neural progenitors which undergo selection and maturation into functional neurons. The induction of these early hippocampal progenitors after injury may represent an endogenous mechanism for brain recovery and remodeling. To determine what role early hippocampal progenitors play in remodeling following injury, we utilized a model of hypoxic-ischemic injury on young transgenic mice that express green fluorescent protein (GFP) specifically in neural progenitors. We demonstrate that this injury selectively activates programmed cell death in committed but immature neuroblasts, which is followed by proliferation of both early type 1 and later type 2 progenitors. This subsequently leads to newly generated neurons becoming stably incorporated into the DG.Hippocampus 08/2008; 18(8):793-806. DOI:10.1002/hipo.20439 · 4.30 Impact Factor
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- "During this time, a vast array of modifying events occurs, simply as a function of infant care. Using a nonhuman primate (baboon) model of preterm birth (gestation day 125) and neonatal intensive care (2–4 weeks) mimicking that used with human infants, Inder et al. (2005) showed a resulting neuropathology characterized by white matter damage, reactive astrogliosis, activated microglia, and ventricular enlargement. These changes occurred in the absence of maternal infection and were associated with the neonatal intensive care protocol. "
ABSTRACT: Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology.NeuroToxicology 10/2006; 27(5):658-70. DOI:10.1016/j.neuro.2006.05.004 · 3.05 Impact Factor