Dr Julia Shaw
School of Biomedical Sciences and Pharmacy
- Phone:(02) 4042 0485
Dr Julia Shaw is a postdoctoral researcher working in the Pregnancy Compromise and Neuroprotection group with the Mothers and Babies Research Centre. Her research examines the role of endocrine disruption following preterm birth on brain development of the offspring, and in particular, focuses on the long-term consequences into childhood and beyond.
She has recently been awarded her PhD in Experimental Pharmacology from the University of Newcastle in 2017. During her PhD, Dr Shaw focused on how a premature loss of placental neurosteroids results in diffuse white matter injury and impairments of the GABAergic system in the juvenile brain following preterm birth. She identified that the hippocampus and cerebellum are particularly vulnerable to these disturbances in brain development and may play a contributing role in the increased rate of behavioural disorders, such as ADHD and anxiety, that are more common following preterm birth.
Dr Shaw is currently investigating the use of a neurosteroid-replacement therapy to prevent these adverse outcomes of preterm birth on brain development.
- Doctor of Philosophy, University of Newcastle
- Bachelor of Biomedical Sciences, University of Newcastle
- Bachelor of Biomedical Sciences (Hons), University of Newcastle
- Preterm Birth
Fields of Research
|111401||Foetal Development and Medicine||40|
|110999||Neurosciences not elsewhere classified||40|
|Title||Organisation / Department|
|Research Associate||University of Newcastle
School of Biomedical Sciences and Pharmacy
For publications that are currently unpublished or in-press, details are shown in italics.
Journal article (7 outputs)
Shaw JC, Palliser HK, Dyson RM, Berry MJ, Hirst JJ, 'Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth', International Journal of Developmental Neuroscience, 65 1-10 (2018) [C1]
© 2017 ISDN Background Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity ... [more]
© 2017 ISDN Background Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity disorder (ADHD). There is increasing interest in the role of the cerebellum in these processes and the potential involvement of GABAergic pathways in neurodevelopmental disorders. We propose that preterm birth, and the associated loss of the trophic intrauterine environment, alters the development of the cerebellum, contributing to ongoing neurobehavioral disorders. Methods Guinea pigs were delivered preterm (GA62) or spontaneously at term (GA69), and tissues collected at corrected postnatal day (PND) 28. Neurodevelopmental and GABAergic markers myelin basic protein (MBP), neuronal nuclei (NeuN), calbindin (Purkinje cells), and GAD67 (GABA synthesis enzyme) were analysed in cerebellar lobules IX and X by immunohistochemistry. Protein expression of GAD67 and GAT1 (GABA transporter enzyme) were quantified by western blot, whilst neurosteroid-sensitive GABA A receptor subunits were measured by RT-PCR. Results MBP immunostaining was increased in lobule IX of preterm males, and reduced in lobule X of preterm females when compared to their term counterparts. GAD67 staining was decreased in lobule IX and X of the preterm males, but only in lobule X of the preterm females compared to term cohorts for each sex. Internal granule cell layer width of lobule X was decreased in preterm cohorts of both sexes compared to terms. There were no differences between gestational age groups for NeuN staining, GAD67 and GAT1 protein expression as measured by western blotting, or GABA A receptor subunits as measured by RT-PCR between preterm and term for either sex. Conclusions The present findings suggest that components of the cerebellar GABAergic system of the ex-preterm cerebellum are disrupted. The higher expression of myelin in the preterm males may be due to a deficit in axonal pruning, whereas females have a deficit in myelination at 28 corrected days of age. Together these ongoing alterations may contribute to the neurodevelopmental and behavioural disorders observed in those born preterm.
Shaw JC, Palliser HK, Palazzi K, Hirst JJ, 'Administration of Progesterone Throughout Pregnancy Increases Maternal Steroids Without Adverse Effect on Mature Oligodendrocyte Immunostaining in the Guinea Pig', Reproductive Sciences, 25 395-405 (2018) [C1]
© 2017, © The Author(s) 2017. Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use,... [more]
© 2017, © The Author(s) 2017. Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (ß-cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta.
Bennett GA, Palliser HK, Shaw JC, Palazzi KL, Walker DW, Hirst JJ, 'Maternal stress in pregnancy affects myelination and neurosteroid regulatory pathways in the guinea pig cerebellum', Stress, 20 580-588 (2017) [C1]
© 2017 Informa UK Limited, trading as Taylor & Francis Group. Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebell... [more]
© 2017 Informa UK Limited, trading as Taylor & Francis Group. Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be linked to hyperactivity disorders. The aims were to determine the effect of prenatal stress on markers of cerebellar development, a key enzyme in neurosteroid synthesis and the expression of GABA A receptor (GABA A R) subunits involved in neurosteroid signaling. We used a model of prenatal stress (strobe light exposure, 2 h on gestational day 50, 55, 60 and 65) in guinea pigs, in which we have characterized anxiety and neophobic behavioral outcomes. The cerebellum and plasma were collected from control and prenatally stressed offspring at term (control fetus: n = 9 male, n = 7 female; stressed fetus: n = 7 male, n = 8 female) and postnatal day (PND) 21 (control: n = 8 male, n = 8 female; stressed: n = 9 male, n = 6 female). We found that term female offspring exposed to prenatal stress showed decreased expression of mature oligodendrocytes (~40% reduction) and these deficits improved to control levels by PND21. Reactive astrocyte expression was lower (~40% reduction) following prenatal stress. GABA A R subunit (d and a6) expression and circulating allopregnanolone concentrations were not affected by prenatal stress. Prenatal stress increased expression (~150¿250% increase) of 5a-reductase type-1 mRNA in the cerebellum, which may be a neuroprotective response to promote GABAergic inhibition and aid in repair. These observations indicate that prenatal stress exposure has marked effects on the development of the cerebellum. These findings suggest cerebellar changes after prenatal stress may contribute to adverse behavioral outcomes after exposure to these stresses.
Hirst JJ, Cumberland AL, Shaw JC, Bennett GA, Kelleher MA, Walker DW, Palliser HK, 'Loss of neurosteroid-mediated protection following stress during fetal life', Journal of Steroid Biochemistry and Molecular Biology, 160 181-188 (2016) [C1]
© 2015 Elsevier Ltd. All rights reserved. Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppr... [more]
© 2015 Elsevier Ltd. All rights reserved. Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppression of allopregnanolone production during pregnancy leads to the onset of seizure-like activity and potentiates hypoxia-induced brain injury. Markers of myelination are reduced and astrocyte activation is increased. The placenta has a key role in maintaining allopregnanolone concentrations in the fetal circulation and brain during gestation and levels decline markedly after both normal and preterm birth. This leads to the preterm neonate developing in a neurosteroid deficient environment between delivery and term equivalence. The expression of 5a-reductases is also lower in the fetus prior to term. These deficiencies in neurosteroid exposure may contribute to the increase in incidence of the adverse patterns of behaviour seen in children that are born preterm. Repeated exposure to glucocorticoid stimulation suppresses 5a-reductase expression and allopregnanolone levels in the fetus and results in reduced myelination. Both fetal growth restriction and prenatal maternal stress lead to increased cortisol concentrations in the maternal and fetal circulation. Prenatal stress results in reduced expression of key GABA A receptor subunits that normally heighten neurosteroid sensitivity. These stressors also result in altered placental allopregnanolone metabolism pathways. These findings suggest that reduced neurosteroid production and action in the perinatal period may contribute to some of the adverse neurodevelopmental and behavioural outcomes that result from these pregnancy compromises. Studies examining perinatal steroid supplementation therapy with non-metabolisable neurosteroid analogues to improve these outcomes are warranted.
Shaw JC, Palliser HK, Dyson RM, Hirst JJ, Berry MJ, 'Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the Guinea pig', Pediatric Research, 80 275-283 (2016) [C1]
© 2016 International Pediatric Research Foundation, Inc. Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral dis... [more]
© 2016 International Pediatric Research Foundation, Inc. Background: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. Methods: Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile Guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABA A) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. Results: Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the a5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. Conclusion: We conclude that juvenile ex-preterm male Guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies.
Bennett GA, Palliser HK, Shaw JC, Walker D, Hirst JJ, 'Prenatal stress alters hippocampal neuroglia and increases anxiety in childhood', Developmental Neuroscience, 37 533-545 (2015) [C1]
© 2015 S. Karger AG, Basel. Prenatal stress has been associated with detrimental outcomes of pregnancy, including altered brain development leading to behavioural pathologies. The... [more]
© 2015 S. Karger AG, Basel. Prenatal stress has been associated with detrimental outcomes of pregnancy, including altered brain development leading to behavioural pathologies. The neurosteroid allopregnanolone has been implicated in mediating some of these adverse outcomes following prenatal stress due to its potent inhibitory and anxiolytic effects on the brain. The aims of the current study were to characterise key markers for brain development as well as behavioural parameters, adrenocortical responses to handling and possible neurosteroid influences towards outcomes in Guinea pig offspring in childhood. Pregnant Guinea pig dams were exposed to strobe light for 2 h (9-11 a.m.) on gestational days 50, 55, 60, and 65 and were left to deliver spontaneously at term and care for their litter. Behavioural testing (open-field test, object exploration test) of the offspring was performed at postnatal day 18 (with salivary cortisol and DHEA measured), and brains were collected at post-mortem on day 21. Markers of brain development myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) were assessed via immunohistochemistry, and the neurosteroid allopregnanolone and its rate-limiting enzymes 5a-reductase types 1 and 2 (5aR1/2) were measured in neonatal brains by radioimmunoassay, reverse transcriptase polymerase chain reaction (RT-PCR), and Western blot, respectively. Brain-derived neurotrophic factor protein was measured as a marker of synaptic plasticity, and GABA A receptor subunit expression was also assessed using RT-PCR. Neonates born from mothers stressed during late pregnancy showed a reduction in both MBP (p < 0.01) and GFAP (p < 0.05) expression in the CA1 region of the hippocampus at 21 days of age. Pups of prenatally stressed pregnancies also showed higher levels of anxiety and neophobic behaviours at the equivalent of childhood (p < 0.05). There were no significant changes observed in allopregnanolone levels, 5aR1/2 expression, or GABA A receptor subunit expression in prenatally stressed neonates compared to controls. This study shows alterations in markers of myelination and reactive astrocytes in the hippocampus of offspring exposed to prenatal stress. These changes are also observed in offspring that show increased anxiety behaviours at the equivalent of childhood, which indicates ongoing structural and functional postnatal changes after prenatal stress exposure.
Shaw JC, Palliser HK, Walker DW, Hirst JJ, 'Preterm birth affects GABA
© 2015 Cambridge University Press and the International Society for Developmental Origins of Health and Disease. Modulation of gamma-aminobutyric acid A (GABA A ) receptor signall... [more]
© 2015 Cambridge University Press and the International Society for Developmental Origins of Health and Disease. Modulation of gamma-aminobutyric acid A (GABA A ) receptor signalling by the neurosteroid allopregnanolone has a major role in late gestation neurodevelopment. The objective of this study was to characterize the mRNA levels of GABAA receptor subunits (a4, a5, a6 and d) that are key to neurosteroid binding in the brain, following preterm birth. Myelination, measured by the myelin basic protein immunostaining, was used to assess maturity of the preterm brains. Foetal guinea pig brains were obtained at 62 days' gestational age (GA, preterm) or at term (69 days). Neonates were delivered by caesarean section, at 62 days GA and term, and maintained until tissue collection at 24 h of age. Subunit mRNA levels were quantified by RT-PCR in the hippocampus and cerebellum of foetal and neonatal brains. Levels of the a6 and d subunits were markedly lower in the cerebellum of preterm guinea pigs compared with term animals. Importantly, there was an increase in mRNA levels of these subunits during the foetal-to-neonatal transition at term, which was not seen following preterm birth. Myelination was lower in preterm neonatal brains, consistent with marked immaturity. Salivary cortisol concentrations, measured by EIA, were also higher for the preterm neonates, suggesting greater stress. We conclude that there is an adaptive increase in the levels of mRNA of the key GABAA receptor subunits involved in neurosteroid action after term birth, which may compensate for declining allopregnanolone levels. The lower levels of these subunits in preterm neonates may heighten the adverse effect of the premature decline in neurosteroid exposure.
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Conference (1 outputs)
Shaw JC, Palliser HK, Dyson RM, Berry MJ, Hirst JJ, 'Ongoing Defects in Cerebellar Development in a Guinea Pig Model of Preterm Birth.', REPRODUCTIVE SCIENCES, Orlando, FL (2017)