Development of the fetal brain can be compromised by a number of adverse influences during gestation. Intrauterine asphyxial insults are one such cause. This proposal aims to characterize the timing and pathophysiology of events surrounding asphyxial encephalopathies originating in utero so that parameters may be identified which are predictive of pathological neuronal death. This is a prerequisite for the development of technologies that could be applied either before or after birth to determine whether intervention with a neuronal rescue therapy is indicated. Considerable variation occurs in the degree and distribution of neuronal loss resulting from asphyxial injury to the fetal brain. It is hypothesized that this is because a number of factors alter the sensitivity of neurons to injury including: severity and nature of the insult, maturation of the fetus, preinsult metabolic status and the pattern of the insult(s). Asphyxial or ischemic injury results in two phases of neuronal loss: primary cell death is associated with the insult itself while delayed neuronal death occurs during a secondary phase some hours later. It is further hypothesized that some biophysical measures recorded after an in utero insult reflect this secondary phase and that varied histological outcomes are predicted by such parameters measured prior to and during this secondary phase. Experiments will use chronically instrumented fetal sheep. Measures of fetal brain function and hemodynamics will include the electroencephalogram, cerebral impedance (a measure of intracellular edema) and near infrared spectroscopy. Outcome will be evaluated histologically.
Specific aim l will examine the effects of maturation, insult severity and preinsult metabolic status on the sensitivity of the fetal brain to an isolated period of cerebral hypoperfusion. This insult excludes the confounding effects of systemic factors and also enables the predictive value of metabolic or biophysical measures to be assessed. Graded periods of hypoperfusion will be induced using a preparation of carotid artery occlusion at 0.65 and 0.8 gestation.
Specific aim 2 will evaluate, in a model of systemic intrauterine asphyxia (umbilical cord compression) at 0.65 gestation, whether cerebrovascular, neural or cardiac biophysical measures can predict neuronal injury and whether there is a different sensitivity of the brain to asphyxial as opposed to hypoperfusion injury.
Specific aim 3 will evaluate, in models of repeated cerebral hypoperfusion and fetal asphyxia, the basis for altered sensitization of the basal ganglia to injury by repetitive insults. We propose that this sensitization is due to a further insult occurring before cerebrovascular or metabolic homeostasis has been restored. Cortical and striatal microdialysis will be used to assess cerebral metabolism and neuromodulator release. These studies will enhance our understanding of the origin and mechanisms of neurological damage occurring in utero. They will characterize the time course of neuronal injury after different types of insult and examine whether biophysical parameters can identify the fetus which might benefit by intervention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (SRC (11))
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University of Auckland
New Zealand
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Bennet, Laura; Booth, Lindsea C; Drury, Paul P et al. (2012) Preterm neonatal cardiovascular instability: does understanding the fetus help evaluate the newborn? Clin Exp Pharmacol Physiol 39:965-72
Bennet, Laura; Booth, Lindsea C; Ahmed-Nasef, Noha et al. (2007) Male disadvantage? Fetal sex and cardiovascular responses to asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 293:R1280-6
Dean, Justin M; Gunn, Alistair Jan; Wassink, Guido et al. (2006) Transient NMDA receptor-mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep. Exp Physiol 91:423-33
Bennet, L; Booth, L; Malpas, S C et al. (2006) Acute systemic complications in the preterm fetus after asphyxia: role of cardiovascular and blood flow responses. Clin Exp Pharmacol Physiol 33:291-9
Mellor, David J; Diesch, Tamara J; Gunn, Alistair J et al. (2005) The importance of 'awareness' for understanding fetal pain. Brain Res Brain Res Rev 49:455-71
Quaedackers, Josine S; Roelfsema, Vincent; Fraser, Mhoyra et al. (2005) Cardiovascular and endocrine effects of a single course of maternal dexamethasone treatment in preterm fetal sheep. BJOG 112:182-91
Guan, J; Bennet, L; Gluckman, P D et al. (2005) Treatment in animal models. Endocr Dev 9:31-43
Fraser, Mhoyra; Bennet, Laura; Gunning, Mark et al. (2005) Cortical electroencephalogram suppression is associated with post-ischemic cortical injury in 0.65 gestation fetal sheep. Brain Res Dev Brain Res 154:45-55
Gerrits, Luella C; Battin, Malcolm R; Bennet, Laura et al. (2005) Epileptiform activity during rewarming from moderate cerebral hypothermia in the near-term fetal sheep. Pediatr Res 57:342-6
Roelfsema, Vincent; Bennet, Laura; George, Sherly et al. (2004) Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. J Cereb Blood Flow Metab 24:877-86

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