top of pageIntrauterine infection and hypoxemia: damage in the developing brain and retina and neuroprotective therapies.
Prenatal insults such as placental insufficiency or intrauterine infection have detrimental effects on the developing fetal brain with the potential to impair neurological development and result in disorders such as cerebral palsy. In an ovine model we have seen a striking link between intrauterine infection (mimicked by exposure to the endotoxin lipopolysaccharide, LPS) and the presence of cerebral white matter injury, similar to that reported in some cases of cerebral palsy. Using techniques including immunohistochemistry, biochemistry, microarray analysis, cytokine assays, stereology and ultrastructural analysis in this model we are currently investigating the contribution of different mechanisms including hypoxemia and proinflammatory cytokines in the manifestation of this injury. The ultimate aim of these studies is to develop intervention strategies to prevent or limit prenatal brain injury.
Photomicrographs of transverse sections from the cerebral hemispheres in control (A, C, E) and LPS-exposed (B, D, F) fetuses at 105 days of gestation. Following LPS-exposure injury was present in both the subcortical (B) and periventricular (F) white matter. (Duncan et al., 2002. Ped. Res. 52: 941-949)
Very low birth weight (VLBW) and small for gestational age (SGA) infants have a increased risk of visual impairment, however little information is available on the aetiology of these impairments. We have shown that a compromised prenatal environment, including hypoxia and infection affects development of the retina and optic nerve. Dopaminergic amacrine neurons have been of particular interest as they are reduced in several models of prenatal compromise and these neurons may be involved in the mechanisms underlying contrast sensitivity, a parameter that is affected in VLBW infants.
Supported by the National Health and Medical Research Council of Australia
Investigation of cerebral development and injury in the prematurely born primate by magnetic resonance imaging and histopathology
The neurodevelopmental outcome of very preterm infants (< 30 weeks gestational age) is of major concern. Whilst advances in perinatal care have significantly improved the survival of the prematurely born infant, it is recognized that up to 50% of these infants face adverse motor, cognitive and behavioral deficits as they approach school age. Periventricular leukomalacia (PVL), the most common cerebral neuropathology observed in premature infants, is thought to underlie these neurobehavioural deficits. Cerebral injury to the hippocampus, cortex and deep grey matter, may also contribute to subsequent neurologic impairments.
The survival rates of very premature infants have improved dramatically as a result of advances in perinatal care, in particular, respiratory support. It is critical that we understand how particular ventilatory therapies may alter the nature and severity of cerebral injury in preterm infants. To provide insight into the relationship between neonatal respiratory care and cerebral injury, we have established a model of premature birth in a non-human primate, the baboon ( Papio sp.).
In a histological and immunohistochemical study of the brain, we have defined the ontogeny of the cerebral hemispheres and cerebellum and the pattern of cerebral injury in the premature baboon nursed with identical neonatal intensive care to that of the human premature infant. The animals sustained a spectrum of neuropathologies including hemorrhage, white matter injury and ventriculomegaly; which are frequently observed in the human premature infant.
Ontogeny of cortical development (Dieni et al., 2004. JNEN. 63(12):1297-1309) Pattern of brain damage (Dieni et al., 2004. JNEN. 63(12):1297-1309)
Ontogeny of cortical development (Dieni et al., 2004. JNEN. 63(12):1297-1309) Pattern of brain damage (Dieni et al., 2004. JNEN. 63(12):1297-1309)
Project A: We are now assessing how the pattern of cerebral injury varies in relation to specific ventilatory regimes including: inhaled nitric oxide, positive pressure ventilation, continuous positive airway pressure and high frequency ventilatory oscillation. We hypothesise that the nature and severity of brain development will vary between animals in relation to their neonatal ventilatory therapy.
Project B: In collaboration with investigators at the University of Washington, St Louis (Assoc Professor Jeff Neil and Dr Chris Kroenke) we are correlating neuropathological alterations with conventional and advanced MRI imaging in the prematurely delivered baboon brain. In addition we are using diffusion anisotropy to monitor the ontogenetic development of the normal primate cerebral cortex. This projects is supported by the National Institutes of Health, USA ; grant RO1 HL074942-01A1
Anisotrophy of the primate brain at 125 days of gestation.
Late gestation fetal alcohol exposure: Physiological, histological and biochemical studies
Alcohol is a well established teratogenic drug. For many decades it has been known that fetal alcohol exposure can result in cognitive impairment, behavioural disturbances, physical abnormalities and neurological damage. Though the detrimental effect of alcohol consumption in pregnancy has been established, the combined rate of Fetal Alcohol Syndrome (FAS) and Alcohol Related Neurodevelopmental Disorder (ARND) is still estimated to be at least 9/1000 live births. Substantial research into fetal alcohol exposure in the past has focused on neuronal loss, interference of neuronal migration and alcohol direct toxic effect on cells in small animal models or in cell culture. This project aims to characterise central nervous system (CNS) damage following a repeated "binge" pattern of alcohol exposure in a large animal model, at a biologically relevant dose. Experiments to date have particularly focused on increased apoptosis and white matter damage in the cerebral hemispheres and cerebellum following alcohol exposure in late gestation. With our observations of CNS damage from this model, we hope to further identify potential mechanisms of alcohol-induced fetal brain damage.
Project supported by the Pratt Foundation, Victoria, Australia.
Rees Lab ~ Publications
2008
•STONE J, V, VALTER K,REES S., PROVIS J. The location of mitochondria in mammalian photoreceptors: relation to the retinal vasculature. Brain Res. (2008) 1189: 58-69
• LOELIGER M., BRISCOE TA.,REES S. BDNF increases survival of retinal dopaminergic neurons after prenatal compromise. IOVS (2008) 49: 1282-9
• DALITZ P., COCK M, HARDING R.,REES S. Injurious effects of acute ethanol exposure during late gestation in developing white matter. IJDN (2008) 26: 391-99
2007
• LOELIGER M., DUNCAN J., COCK M., HARDING R., REES S. Vulnerability of dopaminergic amacrine cells and optic nerve myelination to prenatal endotoxin exposure. Invest Opthalmol Vis Sci 48(1): 472-8 (2007)
2006
• LOELIGER M., INDER T., CAIN S., RAMESH RC., CAMM E., THOMSON MA., COALSON J., REES SM. Cerebral outcomes in a preterm baboon model of early versus delayed nasal continuous positive airway pressure. Pediatrics 118(4): 1640-53 (2006).
• BRISCOE TA., TOLCOS M., DIENI S., LOELIGERM., REES SM. Prenatally compromised neurons respond to brain-derived neurotrophic factor in vitro. Neuroreport 17(13): 1385-9 (2006).
• NITSOS, I. , REES, SM., DUNCAN, J., KRAMER, BW., HARDING, R., NEWNHAM, JP., MOSS, TJ. Chronic exposure to intra-amniotic lipopolysaccharide affects the ovine fetal brain. J. Soc. Gynecol. Invest. 13(4): 239-47 (2006).
• DUNCAN JR., COCK ML., SUZUKI K., SCHEERLINCK JP., HARDING R., REES SM. Chronic endotoxin exposure causes brain injury in the ovine fetus in the absence of hypoxemia. J. Soc. Gynecol. Invest. 13(2): 87-96 (2006).
• BRISCOE T., DUNCAN J., COCK C., CHOO J., RICE G., HARDING R., SCHEERLINCK JP., REES S. Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS-exposure. J. Neurosci. Res. 83(4): 567-74 (2006).