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COLLEGE STATION -- A mother's alcoholic binge in late pregnancy could make her unborn child -- or at least its brain -- old before its time, researchers say. In studies of laboratory rats, researchers at Texas A&M University's College of Medicine have found that exposure to high doses of alcohol during the equivalent of the last three months of human pregnancy causes changes in the animals' brains and behavior that look a lot like old age. "We are seeing changes in circadian rhythms, such as the sleep-wake cycle, that are reminiscent of changes associated with aging," says Texas A&M neurobiologist David J. Earnest. "In essence, the ethanol exposure is accelerating the aging of the biological clock in the brain that controls 24-hour or circadian rhythms." The Texas A&M researchers noted permanent changes both in the rats' sleep-wake cycles and in levels of an important brain chemical associated with regulation of circadian rhythms. Earnest described the research in a paper presented to the 1997 annual meeting of the Society for Neuroscience Oct. 25-30 in New Orleans. Earnest and colleagues Jo Mahoney, Wei-Jung Chen, Farida Sohrabji and James West examined the effects on the brain of high doses of alcohol administered during the first few days after the rats were born, a period during which the rats' brains develop at the same rapid rate that occurs during last three months of human pregnancy. They found permanent changes in the rat sleep-wake cycle, changes similar to those experienced by normal rats -- and humans -- in old age. In alcohol-treated animals, their activity began much earlier each day due to a shortening of the circadian period of the sleep-wake cycle. Their activity also was more fragmented, with frequent alternation between short intervals of sleep and waking. This alcohol-induced change in circadian behavior was strongly associated with marked decreases in the amount of brain-derived neurotrophic factor (BDNF) in the biological clock located in the suprachiasmatic nucleus (SCN). BDNF is a growth factor associated with neural development, but it also appears to maintain cell functioning in the adult brain. These aging-like changes in the SCN are unusual, Earnest says. In some brain regions, alcohol exposure was actually found to increase production of BDNF. Alcohol also induces other enduring changes in the brain, but the associated alterations in physiology and behavior usually reflect a delay in development. This contrasts with the long-term changes in circadian rhythms that accompany the permanent effects of alcohol on BDNF levels in the SCN. Earnest and his colleagues first identified a specific function for BDNF in the regulation of circadian rhythms by the clock in the SCN by using mice with genetically engineered reductions in BDNF levels that show altered circadian rhythms comparable to those induced by aging and alcohol, says Earnest. "During the normal aging process you're going to see these sorts of changes in the circadian period, particularly in the sleep-wake cycle," he says. "But with the added factor of fetal ethanol exposure, you have the potential for a combined effect and consequences for the disturbance in sleep-wake cycle and circadian rhythms in general may be even more dramatic." Earnest noted that understanding whether specific changes in the biological clock in the brain may be responsible for these alterations in circadian rhythms and the sleep-wake cycle could have important implications for human mental health and performance. "Sleep disturbances are a significant health problem for millions of Americans," Earnest says. Sleep-wake disorders are the second-leading cause of institutionalization of older persons in the United States, Earnest says. Perturbations in the sleep-wake cycle often occur in the elderly and especially in people with Alzheimer's disease. Sleep disturbances are also a contributing factor in clinical depression. They affect the workplace through the loss of productivity and increased accidents. Several of the largest human disasters of this century, such as the grounding of the supertanker Exxon Valdez and the Chernobyl nuclear reactor meltdown, can be linked to human error from shiftwork-related fatigue. Earnest noted that fetal alcohol syndrome was first characterized in humans in 1973, and researchers still have only limited understanding of what areas of the fetal brain and what associated behaviors in humans are specifically affected by alcohol. Further studies will be needed to understand whether fetal alcohol exposure induces similar, long-term changes in human circadian rhythms and what are the behavioral consequences of those changes, Earnest says. These studies also give new insight into critical functions that BDNF may have on the brain center -- the SCN -- responsible for regulating circadian rhythms, Earnest says. Current studies are exploring whether genetically engineered SCN cells that express BDNF could provide a "fountain of youth" and restore normal circadian rhythms -- especially normal sleep-wake cycles -- in aged people. Preliminary studies of laboratory animals suggest that transplanting these cells into the area of the brain that controls circadian rhythms has potential for reversing some of age-related sleep disturbances.
By Gene Charleton
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