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Browsing by Subject "Fetal Alcohol Spectrum Disorder"
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Item Effects of coadministration of D-Napvsipq [NAP] and D-Sallrsipa [SAL] on spatial learning after developmental alcohol exposure(2013) Wagner, Jennifer Lynne; Goodlett, Charles R.; Neal-Beliveau, Bethany S.; Grahame, Nicholas J.; Powley, T. L. (Terry L.)Despite warnings about the dangers of drinking during pregnancy, little progress has been made in reducing alcohol drinking among women of childbearing age. Even after the recognition of pregnancy, 15% of women continue to drink, 3% of which admit to binge drinking. Because we cannot stop women from drinking during pregnancy, and many children with fetal alcohol spectrum disorders (FASD) are adopted, there is a significant need to develop postnatal interventions that can improve the long-term outcome of children adversely affected by prenatal alcohol exposure. This thesis aims to evaluate one promising new treatment in the rehabilitation or rescue of specific learning deficits long after the damage has occurred. The treatment evaluated herein (40µg D-NAP + 40µg D-SAL) has long been used in the prevention of the detrimental effects of long-term and binge-like alcohol exposures in rodent models of fetal alcohol syndrome and FASD. Until recently this peptide treatment had only been shown to be effective in preventing some of the consequences of alcohol exposure when administered concurrently with the prenatal alcohol exposure. A recent report by Incerti and colleagues (2010c), however, reported that these peptides could completely reverse a profound spatial learning deficit induced by one episode of a heavy binge-like alcohol exposure (5.9g.kg in a single intraperitoneal injection) on gestational day 8 (G8) in C57BL/6 mice. In that report, the peptide treatment was administered starting in late adolescence, beginning three days prior to and throughout water maze training, and the profound deficits in their alcohol-placebo group were completely eliminated in the alcohol-peptide group. There are currently no FDA-approved treatments for FASD. An effective treatment for the cognitive and behavioral dysfunctions suffered by the 1% of people born today could potentially improve the lives of millions of children and adults. The first aim of this thesis was to determine whether the peptide treatment could reverse the significant spatial learning deficits we have demonstrated in adult C57BL/6 mice given high-dose binge-like alcohol exposure (2.5 g/kg in each of two intraperitoneal injections separated by two hours) on postnatal day (P)7. When administered three days prior to and throughout water maze testing (P67-76), the peptide treatment had no effect on spatial learning. The second aim sought to determine whether the same peptide treatment could reverse water maze spatial learning deficits in G8 binge-like exposure models, as reported by Incerti et al. (2010c). For this analysis, the first study used a different binge-like alcohol exposure model that is more commonly used than that employed by the Incerti et al. (2010c) study, namely administration of 2.8g/kg in each of two intraperitoneal injections separated by four hours (Sulik et al., 1981). This model has been shown to produce high peak blood alcohol concentrations and neuroanatomical aberrations in the hippocampal formation and septal regions (Parnell et al., 2009), which have been implicated in learning and memory. Surprisingly, this G8 binge-like alcohol exposure failed to produce a spatial learning deficit, undermining the usefulness of this model in evaluating the peptide effects. In direct contrast to the outcomes of Incerti et al. (2010c), the G8 Webster alcohol exposure was also unable to produce any deficits in acquisition of spatial learning in the Morris water maze. Surprisingly, neither of the heavy binge-like alcohol exposures on G8 were able to produce spatial learning deficits in the Morris water maze. The binge-like alcohol exposure on P7 did yield the expected spatial learning deficit, but the peptide treatment was unsuccessful in recovering water maze learning. These findings fail to support oral administration of 40µg D-NAP and 40 µg D-SAL as a potential therapy for postnatal alcohol-induced spatial learning deficits in adult mice.Item Ethanol-induced Retinal Defects are Rescued by Retinoic Acid Supplement in Developing Zebrafish Embryos(Office of the Vice Chancellor for Research, 2013-04-05) Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A.Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing a spectrum of defects including facial abnormalities, sensory (visual and auditory) deficits, impaired fine motor skills and learning deficits including mental retardation. Our laboratory has used a zebrafish model for FASD that exposes embryos to ethanol during early development (midblastula transition through somitogenesis). Children diagnosed with FASD frequently show severe eye defects ranging from small eyes, underdeveloped optic nerve, and cataract. Zebrafish embryos exposed to ethanol showed defects similar to human eye birth defects. Presence of ethanol affected the differentiation of many retinal cell types including, retinal ganglion cells and photoreceptors. We hypothesize that ethanol may affect retinal patterning by competing with Retinaldehyde dehydrogenase (Raldh), reducing retinoic acid (RA) synthesis and signaling. Co-treatment of embryos with ethanol and 10-9 M RA could rescue the photoreceptor and retinal ganglion cell differentiation defects in the retina. RA plays a crucial role in the dorso-ventral patterning of the retina, and the enzymes involved in RA biosynthesis are expressed in the ventral retina during mid-somitogenesis stage. Our experiments showed that ethanol exposure during that critical time window when Raldh is expressed in the ventral retina causes severe defects in retinal cell specification. No defects were induced by ethanol exposure at the earlier stages. Presence of RA during photoreceptor differentiation could rescue ethanol-induced photoreceptor differentiation defects. Future work will dissect molecular mechanisms underlying ethanol defects, including retinoic acid-mediated eye development mechanisms. Determining the effects of ethanol exposure on retinal morphogenesis and differentiation will help identify potential therapeutic targets for ocular defects in this regrettably frequent birth defect syndrome.