Year of Publication
Doctor of Philosophy (PhD)
Arts and Sciences
Dr. Susan Barron
Exposure to alcohol (ethanol (ETOH)) during fetal development results in a variety of cognitive/behavioral deficits. The effects of fetal ETOH exposure vary across individuals and numerous studies have shown that ETOH’s interaction with other variables can affect outcome in offspring. These studies investigated the effects of developmental ETOH and hypoxia. It was hypothesized that a history of ETOH during development alters the response to a subsequent hypoxic challenge, such as that which may occur during parturition; this results in central nervous system (CNS) damage and behavioral deficits.
The first study determined if developmental ETOH and hypoxia exposure produced behavioral deficits in a 3rd trimester rodent model. Prior research indicated that chronic ETOH exposure followed by a brief hypoxic challenge produced multiplicative cytotoxicity in an in vitro organotypic hippocampal slice culture (OHSC) model. In vivo, ETOH exposure followed by hypoxia increased locomotor activity in an open field task, compared to controls or subjects exposed to either insult alone. Additionally, ETOH + hypoxia produced acquisition deficits in male subjects in a water maze task.
The second study further investigated ETOH + hypoxic cell damage in the OHSC model. The results from these experiments showed that cytotoxicity increased above control levels over 24 hours in the sensitive CA1 and CA3 regions of the hippocampus. Results also demonstrated that at a relatively “low” concentration of ETOH still sensitized the developing brain to a hypoxic episode. Finally, these data indicate that ETOH withdrawal was necessary to produce an interaction between these two insults.
The third study employed the novel compound, JR220, to determine to role of polyamines in ETOH + hypoxia cytotoxicity in OHSCs. JR220 acts on the polyamine site of NMDAr and previous studies indicate that it is protective against ETOH withdrawal damage. The results from this study suggested that polyamine site blockade was protective against cell damage associated with exposure to ETOH and acute hypoxia.
Collectively, these results indicate that exposure to ETOH during development sensitizes the brain to a brief hypoxic challenge. These results could help explain why some children appear to be more affected by fetal ETOH exposure than others. Both the in vitro and in vivo models developed in this dissertation can be used to further explore the effects of ETOH and hypoxia during fetal development and can be used to screen potential pharmacotherapies.
Carter, Megan L., "THE EFFECTS OF ALCOHOL AND HYPOXIA EXPOSURE IN THE DEVELOPING BRAIN" (2015). Theses and Dissertations--Psychology. 83.