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Description
Prenatal alcohol exposure leads to long-lasting deficits in learning and memory as well as hyperactivity. Using a rat model, we have previously shown that choline supplementation during early development can reduce the severity of fetal alcohol spectrum disorders (FASD), including deficits in learning and memory. Choline is a quatranary amine, classified as an essential nutrient. It subserves various signaling pathways, as a precursor for platelet-activating factor, sphingosylphosphocholine, diacylglycerol, and the neurotransmitter acetylcholine. It is not yet known how choline is able to mitigate alcohol-related learning deficits; however, defining these mechanisms could lead to the identification of additional treatments for FASD. It is hypothesized that choline mitigates alcohol-related learning and memory deficits, in part, by altering cholinergic signaling in the hippocampus, a CNS structure well-known for its role in memory formation and consolidation. To test this hypothesis, quantitative autoradiography was used to measure hippocampal density of M1 and M2 muscarinic receptor subtypes that bind acetylcholine. Sprague-Dawley rat pups were orally intubated with ethanol (5.25mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human 3rd trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. After choline treatment was complete, ambulatory behavior was assessed in an open field chamber for 1 hour per night from PD 30-33. Brain tissue was collected on PD 35 for autoradiographic analysis. Behavioral analysis revealed that ethanol-exposed subjects were more active compared to controls during the first two days of testing; however, activity levels of ethanolexposed subjects treated with choline were not statistically different from that of controls. Physiologically, developmental alcohol exposure significantly decreased the density of muscarinic M1 receptors, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M2 receptor density, an effect mitigated by choline supplementation. In fact, M2 receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. Furthermore, neonatal choline exposure significantly increased choline transporter density in the hippocampus. These data suggest that perinatal alcohol exposure can cause long-lasting changes in the development of the cholinergic system.. This study further shows that choline supplementation may attenuate alcohol-related behavioral changes by normalizing cholinergic function, possibly by increasing the availability of choline for acetylcholine synthesis.
