Developmental Brain Research
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Professor Sandra Rees - Honorary Professorial FellowPhone: 61-0421677952 |
Sandra Rees is an Honorary Professorial Fellow in the Department of Anatomy & Neuroscience at the University of Melbourne. She joined the academic staff at this University in 1992 after holding research positions in the Department of Physiology, Monash University for over 20 years. She retired from the academic staff in 2009, but still keeps an interest in research as a consultant and is actively involved in writing papers and reviews.
Research Interests
There is now compelling evidence that many neurological disorders which become apparent after birth have their origins during fetal life. For example, epidemiological studies have shown that cerebral palsy, a group of non-progressive motor impairment disorders, most frequently results from prenatal rather than perinatal or postnatal causes.
Minimal cerebral brain dysfunction, typified by children having general reading writing and cognitive problems, is often associated with intra-uterine growth restriction (IUGR) suggesting that the neurological problems have their origins in utero. Schizophrenia, one of the most debilitating of mental disorders, affecting ~1% of the population, cannot be accounted for entirely by genetic inheritance.
On the basis of histological and neurochemical observations it has been proposed that prenatal insults result in a vulnerability of the developing brain, predisposing an individual with risk factors (such as genetic inheritance) to develop the symptoms of schizophrenia in the teenage or young adult years. Other disorders such as epilepsy and autism are also thought to result in part from neurodevelopmental problems. Thus, there is growing evidence that abnormal development of the brain during gestation contributes to many neurological disorders which manifest in later life.
In order to understand the mechanisms involved in these forms of abnormal development it is necessary to develop animal models. The focus of my research work has been to develop models of premature birth and prenatal insults including hypoxia, malnutrition, infection and alcohol exposure. By studying their effects on the structure and function of the central nervous system (including the retina) we are now in a position to develop strategies to ameliorate and/or prevent the damaging effects of perinatal brain injury.
Intrauterine 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.
top of pageLate 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
2011
•REES, S., LOELIGER ,M., SHEILDS, SHAUL,P.,A.MC CURNIN,D., YODER,B., INDER,T. The effects of postnatal estrogen therapy on brain development in preterm baboons. Am J Obstet &Gynecol(2011) 204: 177.e 8-14
•NITSOS,I., NEWNHAM,J.,REES,S., HARDING,R., MOSS,JM. The impact of chronic intrauterine inflammation on the physiologic and neurodevelopmental consequences of intermittent umbilical cord occlusion in fetal sheep. (2011) Reprod Sci March 18
•KENNA,K., DE MATTEO,R., HANITA,T., REES,S., SOZO,F., STOKES, V., WALKER, D., BOCKING,A., BRIEN,J., HARDING,R. Daily ethanol during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology . Am J Physiol Regul Integr Comp Physiol ( 2011) 301: R926-936
•LOELIGER,M., MACKINTOSH,A., DE MATTEO,R., HARDING,R., REES,S. Erythropoetin protects the developing retina in an ovine model of endotoxin-induced retinal injury. Invest Ophthal &Vis Sciences (2011) 52: 2656-61
•KUMAR,G., JONES NC., MORRIS MJ., REES S., O`BRIEN TJ.,SALZBERG,.M. Early life stress enhancement of limbic epileptogenesis in adult rats: mechanistic insights. Plos One (2011);6(9)e24033Epub 2011Sep 21
•TOLCOS, M., BATEMAN, E.,O`DOWD,R., MARKWICK,R.,VRIJSEN,K.,REHN,A.,REES,S
Exp Neurol 232(1)53-65 GRIFFITH, JL.,COUSINS SA., REES S ., MCCURNIN,DC., INDER,TE., JEFFREY J NEIL MR Imaging correlates of white matter pathology in the preterm baboon model (2011) Ped Res (in press)
2010
•PROBYN, M., COCK, M., DUNCAN, J., TOLCOS, M., REES, S., HARDING, R. The anti-inflammatory agent N-acetyl cysteine exacerbates endotoxin-induced hypoxemia and hypotension and induces polycythemia in the ovine fetus. Neonatology (2010) 98: 118-127
•REES, S., HALE, N., DE MATTEO, R., CARDAMONE, L., TOLCOS, M., LOELIGER, M., MACKINTOSH, A., SHIELDS, A., PROBYN, M., SCHEERLINCK, J-P., HARDING, R. Erythropoietin is neuroprotective in a preterm ovine model of endotoxin-induced brain damage. J Neuropathol Exp Neurol (2010) 69: 306-319
•Dijkstra, F., Jozwiaka, M., De Matteo, R., Duncan, J., Hale, N., HARDING, R., Rees, S. Erythropoietin ameliorates damage to the placenta and fetal liver induced by exposure to lipopolysaccharide. Placenta (2010) 31: 282-288
•Verney, C., REES s., BIRAN, V., THOMPSON, M., INDER, T., GRESSENS, P. Neuronal damage in the preterm baboon: impact of the mode of ventilatory support. J Neuropathol Exp Neurol (2010) 69:473-482
•Doyle, L.W., Chong,J., Hunt D,W., Lee, KJj., Thompson, D.K., Davis,P.G., Rees, S., Anderson P.J., and Inder,T. Caffeine and brain development in very preterm infants Ann Neurol (2010) 68:734-42
•LOELIGER ,M., SHEILDS,A.MC CURNIN,D., CLYMAN,RI., YODER,B, INDER,T.,REES,SM.Ibuprofen treatment for closure of patent ductus arteriosus is not associated with increased risk of neuropathology. Pediatric Res (2010) 68: 298-302
2009
•Loeliger, M., Inder, T., Dalitz, P., Cain, S., Camm, E., Yoder, B., Mccurnin, D., Shaul, P., Clyman,Rr., Rees, S. Developmental and neuropathological consequences of ductal ligation in the preterm baboon. Pediatric Res (2009) 65:209-214
•BUI, B., LOELIGER, M., THOMAS, M., VINGRYS, A., REES, S., NGUYEN, C., HE, Z., TOLCOS, M. Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats. Exp Eye Res (2009) 88: 1076-1083
•MUNRO K., REES, S., O’DOWD, R., TOLCOS, M. Developmental profile of erythropoietin and its receptor in guinea-pig retina. Cell Tissue Res (2009) 336: 21-29
•REES, S., LOELIGER, M., MUNRO, K., SHIELDS, A., DALITZ, P., DIENI, S., THOMPSON, M., COALSON, V., INDER, T. Cerebellar development in a baboon model of preterm delivery: Impact of specific ventilatory regimes. J Neuropathol Exp Neurol (2009) 68:605-615
•Jones N.C., Kumara, G., O’Brien, T.J., Morris, M.J., Rees, S., Salzbergf, M.R. Anxiolytic effects of rapid amygdala kindling, and the influence of early life experience in rats. Behav Brain Res (2009) 203: 81-87
•LOELIGER, M., INDER, T.E., SHIELDS, A., DALITZ, P., CAIN, S., YODER, B., REES, S. High-frequency oscillatory ventilation is not associated with increased risk of neuropathology compared with positive pressure ventilation: a preterm primate model. Pediatric Res (2009) 66: 545-550
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