Alcohol ’binges’ in rats during early brain development cause circadian rhythm problems

In a study believed to have implications for children and adults suffering from Fetal Alcohol Syndrome, rat pups given alcohol during a period of rapid brain development demonstrated significant changes in circadian or 24-hour rhythms as adults. The alcohol dosage was the equivalent of several nights of binge drinking on the part of a pregnant woman, and it was given at a time during rat brain development (shortly after birth) equivalent to the third trimester of human fetal development.

Dr. David J. Earnest, Texas A&M University Health Sciences Center, presented the findings Sunday, April 3, at an American Association of Anatomists’ session on dissecting the biological clock during Experimental Biology 2005 in San Diego.

Dr. Earnest says the findings are significant for three reasons:

• First, they demonstrate for the first time that the damaging effects of alcohol exposure during brain development impinge on the part of the brain responsible for circadian rhythmicity, the body’s night/day clock and the mechanism through which it regulates various physiological processes throughout the body and types of behaviors.
• Second, the findings may help shed new light on why many children and adults with Fetal Alcohol Syndrome (FAS) have altered sleep wake cycles, attention deficit and hyperactivity disorders, and display other disruptions in behavior.
• And third, the changes in circadian rhythms caused by developmental alcohol exposure may affect chronotherapeutic treatment of diseases because the efficacy and side effects of many drugs are known to depend on the time of administration in relation to normal body rhythmicity.

Fetal Alcohol syndrome (FAS) can occur in the offspring of mothers who abuse alcohol during pregnancy. Some of the deleterious effects of maternal alcohol use on the developing fetus include craniofacial alterations (e.g. a thin upper lip and a small nose) and defects in brain development. Animal studies examining the spectrum of alcohol-induced brain injuries have revealed that affected offspring are most vulnerable to the damaging effects of alcohol during the brain growth spurt period, which is the human equivalent of the third trimester and that these defects in brain development often persist into adulthood.

Unlike the craniofacial differences sometimes seen in FAS children (which may lessen into adolescence and adulthood), the impact of alcohol on brain function as the child grows is less measurable and knowledge of the timing and amount of alcohol consumed during pregnancy is based only on the account of the mother. Dr. Earnest says animal studies using a rat model provide a way to obtain clearer information as well as focus on potential disturbances in a specific brain function – circadian rhythms – that has not been studied in relationship to FAS but which has implications for FAS and, indeed, for all of us.

During this period equivalent to the third trimester in humans, rat pups were given either formula or mixture formula containing alcohol that raised the pups’ blood alcohol levels equivalent to what human fetuses experience during binge drinking episodes on the part of their mother.

As adults, the rats that had been exposed to alcohol during brain development showed similar activity levels as rats of the same age that had not experienced alcohol. But the rats exposed to alcohol showed a number of remarkable changes in the circadian rhythm of activity that put them on a different schedule and pattern than other rats.

Rats are nocturnal animals and normally begin their activity slightly after darkness sets in. The rats that had been exposed to alcohol began activities slightly before darkness set in.

When normal rats – or for that matter, humans and other animals – are in situations without environmental cues about day and night, the body’s circadian clock generally drives behaviors on a cycle slightly greater than 24 hours. Untreated animals woke up approximately 20 minutes later each day in the absence of a light-dark cycle. The rats that had been exposed to alcohol consistently became active 30 minutes earlier every day.

In situations when the light-dark cycle was shifted six hours earlier, the “jet lag” equivalent for humans having to shift their body clocks when traveling across different time zones, the rats exposed to alcohol in infancy shifted much more quickly, as they did to 15-minute light pulses. While this may sound good to most traveling humans, it reflects permanent changes that have ramifications on how systems in the body function in relation to each other, says Dr. Earnest.

The researchers also were able to measure changes in the expression of genes related to the clock timing these cycles in the brain and in peripheral tissues, such as the liver, that need to coordinate their own physiological activities with the core clock in the brain.