Studies of human with fetal alcohol syndrome (FAS) and rats with experimental FAS show that the structure and the function of the brain are profoundly affected by prenatal exposure to ethanol. Ethanol-induced defects include microencephaly, a thinner cerebral cortex, and reductions in the number of cortical neurons. Each of these findings may result from a single cause-toxic effects of ethanol that cause neuronal death. The number of neurons in the central nervous system (CNS) is determined by the addition of neurons via cell proliferation and migration and by the loss of neurons due to their death. We will test thy hypothesis that prenatal exposure to ethanol increases the amount of neuronal death in the developing nervous system. Three groups of rats will be used: rats will be fed a liquid ethanol-containing diet, pair-fed an isocaloric liquid control diet, or fed chow and water. In the first experiment, the effect of prenatal exposure to ethanol on neuronal death in cerebral cortex will be examined. We will (a) perform a light microscopic analysis of the morphology of dying neurones identified with a monoclonal antibody, ALZ-50 or a silver staining technique and (b) use an immuno-electron microscopic method and a gold- toning technique to analyze the ultrastructure and synaptology of dying neurons. (c) We will determine the spatiotemporal sequence of neuronal death by documenting the changes in the total number of cortical neurons in a defined segment of cortex. In addition, we will calculate the effects of ethanol on the numbers of ALZ-50-positive, addition, silver- stained, and pyknotic neurons in the same cortical segment. (d) We will perform a biochemical examination of the temporal expression of ALZ-50- immunoreactivity. In the second experiment, we will determine if other CNS structures are affected as is cortex. We will repeat most of the above studies using the principal sensory nucleus of the trigeminal nerve (PSN). The advantage of studying the PSN is that it is a simpler structure containing a more homogeneous population of neurons than cortex and it is composed of a countable number of neurons. Moreover, the PSN represents the focus of CNS and craniofacial malformations characteristic of FAS. In the third experiment, we will test the hypothesis that ethanol-induced neuronal death result from alterations occurring early in development. We will examine the effects of ethanol upon the time of origin of dying neurons and upon the relationship of neuronal migration and neuronal death. We will examine the effects of ethanol on the survival of ectopic neurons and appropriately migrated neurons and the extracellular matrix which impacts on neuronal migration. The proposed experiments are a focussed study into a mechanism of FAS and a test of the hypothesis that the CNS defects associated with FAS result from ethanol-induced increases in neuronal death.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Schools of Medicine
Iowa City
United States
Zip Code
Akinmboni, T O; Davis, N L; Falck, A J et al. (2018) Excipient exposure in very low birth weight preterm neonates. J Perinatol 38:169-174
Wellmann, Kristen A; George, Finney; Brnouti, Fares et al. (2015) Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure. Behav Brain Res 286:201-11
Bearer, Cynthia F; Wellmann, Kristen A; Tang, Ningfeng et al. (2015) Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure. Cerebellum 14:413-20
Hicks, Steven D; Lewis, Lambert; Ritchie, Julie et al. (2012) Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations. BMC Neurosci 13:128
(2012) Retraction statement. Paper by Michael W. Miller and Huaiyu Hu [Developmental Neuroscience 2009;31:50-57]. Dev Neurosci 33:548
Meszaros, Zsuzsa Szombathyne; Dimmock, Jacqueline A; Ploutz-Snyder, Robert et al. (2011) Accuracy of self-reported medical problems in patients with alcohol dependence and co-occurring schizophrenia or schizoaffective disorder. Schizophr Res 132:190-3
Hicks, Steven D; Miller, Michael W (2011) Effects of ethanol on transforming growth factor ?1-dependent and -independent mechanisms of neural stem cell apoptosis. Exp Neurol 229:372-80
Mooney, S M; Miller, M W (2011) Role of neurotrophins on postnatal neurogenesis in the thalamus: prenatal exposure to ethanol. Neuroscience 179:256-66
Mooney, Sandra M; Miller, Michael W (2010) Prenatal exposure to ethanol affects postnatal neurogenesis in thalamus. Exp Neurol 223:566-73
Lindke, Amanda L; Middleton, Frank A; Miller, Michael W (2010) Regulating the availability of transforming growth factor ß1 in B104 neuroblastoma cells. Exp Neurol 225:123-32

Showing the most recent 10 out of 102 publications