Doctors have long recommended that pregnant women avoid smoking. Among the many reasons is a link between early nicotine exposure and attention deficit hyperactivity disorder. A recent study in Nature Neuroscience by Yale researchers helps explain the connection between the nicotine in tobacco and these observed behavioral changes in children.

“I’m interested in the molecules that are responsible for complex behaviors,” said Marina Picciotto, Ph.D., the Charles B.G. Murphy Professor of Psychiatry. “The messiness of behavior is what makes neuroscience so interesting because there’s so much to know.” Her team’s most recent discovery began with a simple observation. They taught mice to avoid a dark chamber by giving them a light shock when they entered. The mice learned quickly—all it took was one trial.

Then they gave a different group of mice a lighter shock that should have been mild enough to ignore. But if they altered the nicotine receptors in the mouse’s brain or gave the mouse nicotine during development, it wouldn’t ignore the shock. In other words, it responded to stimuli that a normal mouse would ignore. This inability to ignore particular stimuli also underlies attention deficit disorder. Picciotto’s interest was piqued.

The team then exposed mice to nicotine early in development and looked for changes in gene expression. “If we can manipulate the function, level, or location of particular molecules we think are important for the cellular and circuit-level function of the brain,” said Picciotto, “we can then ask questions about what that does to behavior in the whole animal.”

After experiments in the lab and computer analysis, Picciotto’s team identified a “master regulator”—a gene that plays a role in controlling gene expression. Early exposure to nicotine, they found, triggered the master regulator, called ASH2L, which led them to the link to behavior—the gene’s role in a process called histone methylation. To form a chromosome, DNA wraps itself around a core of histone proteins. If this process is altered, it can affect the transcription of genes. Early nicotine exposure altered histone methylation at sites along the genome responsible for processes like the regulation of synapses. This explained on a biochemical level why early nicotine exposure could affect behavior.

But Picciotto and her team took it a step further. They wanted to see the biochemical mechanism in action. They had already seen that the mice exposed to nicotine couldn’t ignore certain stimuli. When they turned off the master regulator in those mice, the animals could ignore the stimuli even after early nicotine exposure.

Then the researchers did the opposite. They turned on the master regulator in mice that were never exposed to nicotine—the mice couldn’t ignore the stimuli. They had uncovered a clear biochemical link between early nicotine exposure and behavior.

“This was a true discovery of a mechanism we did not know existed,” Picciotto said.