Dissertation
Role of the genes, NOS1 and CREB1, in a mouse model of fetal alcohol syndrome
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.006035
Abstract
Alcohol-exposure during pregnancy can kill developing neurons and lead to fetal alcohol spectrum disorder (FASD). However, affected individuals differ in the regional pattern and severity of their alcohol-induced neuropathology. Twin studies have confirmed that genetic differences account for much of FASD’s heterogeneity. To dissect these differences, later work has focused on genes, such as nNOS and CREB, that occupy critical nodes of canonical cell signaling pathways enhancing neuronal survival. The primary goal of this thesis is to study how nNOS and CREB can alter the pattern, severity, and behavioral consequences of alcohol-induced damage using somatic and cell-specific knockout mouse models. Somatic removal of nNOS had different regional effects. Cells of the olfactory bulb, a region that strongly expresses (nNOS), became highly vulnerable after deletion of nNOS. In contrast the facial nerve nucleus, where nNOS is not expressed, did not change in vulnerability after deletion of nNOS. Removal of CREB from Purkinje cells, slightly reduced their number, worsened alcohol-induced loss of the Purkinje cells, and worsened alcohol-induced performance deficits on the rotarod and balance beam. The alcohol-induced loss of granule cells was unaffected by presence or absence of CREB in Purkinje cells. These results underscore the role of genetics in fetal alcohol syndrome, particularly in the presence or absence of neuroprotective genes. The variation in expression of these genes may underlie the heterogeneity found in FASD, and treatments that target related cellular pathways could protect the fetal brain against injury after alcohol exposure.
Details
- Title: Subtitle
- Role of the genes, NOS1 and CREB1, in a mouse model of fetal alcohol syndrome
- Creators
- Dylan Weston Todd
- Contributors
- Daniel J Bonthius (Advisor)Alexander G Bassuk (Committee Member)Michael E Dailey (Committee Member)Charles Harata (Committee Member)John A Wemmie (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.006035
- Publisher
- University of Iowa
- Number of pages
- x, 109 pages
- Copyright
- Copyright 2020 Dylan Weston Todd
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 95-109).
- Public Abstract (ETD)
Fetal alcohol spectrum disorders (FASD) are conditions that can occur when a fetus is exposed to alcohol during gestation. Alcohol exposure damages the developing brain and can result in intellectual disability, seizures, and loss of coordination. It is unclear why there is a wide range of FAS severity in children with similar levels of alcohol exposure. One potential explanation is the genetic background of the fetus. Previous work has shown that certain genes such as nNOS and CREB can influence the developing brain’s vulnerability to alcohol. Using mutant mice that lack nNOS or mice that lack CREB specifically in the Purkinje cells of the cerebellum, I hypothesize that removal of these genes will increase vulnerability to alcohol.
When nNOS was removed from neurons, the effect varied greatly by region. Cells of the olfactory bulb, which ordinarily produce nNOS at high levels, were made highly vulnerable to alcohol after deletion of nNOS. Cells of the facial nucleus, which do not produce nNOS, exhibited no change in vulnerability to alcohol after the deletion of nNOS. This suggests that nNOS plays a protective role only in cells that ordinarily express it. Purkinje cell specific deletion of CREB worsened both alcohol-induced loss of the Purkinje cells and motor behavior. These results confirm the importance of genetics in the development of fetal alcohol syndrome. Furthermore, this research suggests that the development of medications that target either of these genes could help protect the brain against alcohol-induced injury.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984097172802771
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