One of the biggest problems of investigating oxidative stress and other mechanisms in the central nervous system is the lack of functional models that reflect the dynamic and living status of the intact animal. This problem is magnified for perinatal studies because the fetus is relatively inaccessible. This proposal introduces an innovative animal model system that uses the olfactory system as a window to the rest of the brain. It addresses the need of doing more studies investigating the effect of hypoxia on olfaction in the perinatal period. In patients with cerebral palsy (CP), sensory disabilities have not received as much attention as motor deficits and this provides a model for studying the issue of sensory disabilities among the postnatal developmental disabilities following fetal hypoxia-ischemia (H-I). Our hypothesis is that the interaction of reactive oxygen species (ROS) with nitric oxide mediates neuronal injury caused by fetal H-I. We will determine live olfactory neuron function in the intact animal using functional magnetic resonance imaging MRI that is based on the uptake of manganese ion in fetal H-I. Nitric oxide (NO) plays a central role in olfaction and is thought to do so by redox regulation with the formation of reactive nitrogen species (RNS). These concepts will be tested using a multidisciplinary approach in a recently developed animal model manifesting a CP phenotype following preterm uterine ischemia mimicking the clinical pathophysiology of acute placental insufficiency. We have previously shown that ROS and RNS are produced in fetal brain after H-I in this model, and administration of antioxidants to the mother ameliorates fetal brain injury.
The first aim characterizes the developmental vulnerability of the olfactory tract to fetal H-I at various gestational ages. Functional MRI using manganese uptake will be correlated with cell injury, death and apoptosis by flow cytometry and immunohistochemical evidence in the olfactory epithelium and olfactory bulbs.
The second aim determines if ROS and RNS mediate injury to the olfactory system caused by fetal H-I. We will test whether the developmental vulnerability is due to ROS by measuring superoxide and lipid peroxidation and/or RNS by S-nitrosylation and nitration of tyrosine. We will test our hypothesis by amelioration of the hypoxic-ischemic injury by decreasing ROS and manipulating levels of NO. The functional recovery of olfactory system will be assessed by serial functional MRI and separate immunostaining of mature olfactory neurons and olfactory bulbs at two postnatal ages. Our objectives are to understand key mechanisms of oxidative stress and redox signaling in neuronal injury from H-I and to ultimately generate the studies for an R-01application. This model system will be valuable in the study of other mechanisms of disease, plasticity, and recovery in the hitherto inaccessible fetus, and prenatal programming of smell in diverse pathologies, such as in obesity. The proposal introduces an innovative animal model system that uses the olfactory system as a window to the rest of the brain, addresses the need of doing more studies investigating sensory deficits such as olfaction in the perinatal period, and investigates a key mechanism of oxidative stress in olfactory injury. This model system will be valuable in the study of other mechanisms of disease, plasticity, and recovery in the hitherto inaccessible fetus and prenatal programming of smell in diverse pathologies. ? ? ?
| Drobyshevsky, Alexander; Yu, Lei; Yang, Yirong et al. (2012) Antenatal insults modify newborn olfactory function by nitric oxide produced from neuronal nitric oxide synthase. Exp Neurol 237:427-34 |
