Novel oxytocin gene expression in the hindbrain is induced by alcohol exposure: transgenic zebrafish enable visualization of sensitive neurons.
BACKGROUND
Fetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported.


RESULTS
The effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area.


CONCLUSIONS
Alcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, United States of America.
Caitrín M
CM
Coffey
Patricia A
PA
Solleveld
Joyce
J
Fang
Antonia K
AK
Roberts
Sung-Kook
SK
Hong
Igor B
IB
Dawid
Caroline E
CE
Laverriere
Eric
E
Glasgow
D000818:Animals; D030801:Animals, Genetically Modified; D000431:Ethanol / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D057054:Molecular Imaging; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010121:Oxytocin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012249:Rhombencephalon / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
D000431:Ethanol; D010121:Oxytocin