The pathway to anxiety begins early in life

May 20, 2002

The circuitry in the brain that leads to anxiety first gets established in early development, according to new findings in mice by researchers from Columbia University Health Sciences and colleagues elsewhere. Their results imply that current popular drugs for adult anxiety do not necessarily treat the cause of the disorder, but may be alleviating symptoms resulting from an event that occurred long ago.

The research, published in the March 28 issue of Nature, reveals there is a window of time during the development of the mouse--between five and 21 days after birth--when the brain becomes wired to be anxious later in life. The comparable time in humans is the third trimester of pregnancy and the first two to three years of life.

The study, led by Dr. Rene Hen, associate professor of pharmacology (in psychiatry and in the Center for Neurobiology and Behavior), focused on a serotonin receptor gene. The researchers manipulated the time in development and the location in the brain that the serotonin receptor was active to understand its role in creating anxiety circuitry.

Brain neurons communicate with each other by secreting chemical messengers--neurotransmitters such as serotonin--which cross the synaptic gulf between nerve cells and bind to receptors on neighboring nerve cell membranes. Once the neurotransmitters bind to the receptors, the nerve cells become activated.

Medications that enhance the binding of serotonin to its receptor (such as the selective serotonin reuptake inhibitors, or SSRIs) work effectively to treat anxiety and depression, suggesting the receptor and the neurotransmitter play a role in regulating these emotions. Since the drugs act by increasing the amount of serotonin in the brain, scientists have presumed the disorders may be due to decreased levels of serotonin in the adult brain.

Mice without the gene for the serotonin receptor, so-called knockout mice, become very anxious, indicating the gene acts normally to prevent anxiety. Highly anxious adult mice move around less than normal in novel open or elevated spaces and are slower to eat food in such novel environments.

Through sophisticated and novel genetic tools, Dr. Hen and his colleagues were able to turn off and on the gene for the serotonin receptor in different locations in the mouse brain and during different times in development. They then could monitor the resulting anxiety-like behaviors in the animals.

First, they identified the locations in the brain that were important for the anxious behavior. When they shut off activity of the receptor in one part of the brain and there was no effect, they surmised the region probably did not have a role in anxiety. Conversely, if they shut down activity and the mouse became anxious, they surmised the region may be important for anxiety. Using this method, the investigators showed that certain types of "anxiety" may be located in the hippocampus and the cortex of the mouse brain. Then they determined what happened if they shut off activity of the serotonin receptor at different times in the mouse's life. Mice without the receptor between five and 21 days after birth, become very anxious as adults, the researchers found. The serotonin receptor acting during that period therefore plays an important role in laying down the normal emotional circuitry of the mouse.

But removing the receptor's activity in an adult mouse did not seem to have an effect on the animal's behavior. The mouse acted normally despite predictions that it would become anxious since the prevailing paradigm suggests that lower levels of serotonin (or no receptor) in the adult brain lead to anxiety.

"The finding implies that a pathway to anxiety is laid down during early development," Dr. Hen says. "And while the drugs work on the adult brain, the primary reason for the anxiety was probably due to an earlier event in the life of a person." The earlier event(s) may have created a milieu in which the nerve cells in the adult are not secreting enough serotonin, he says, but the research shows an adult brain without the serotonin receptor creates normal behavior.

Other behavioral research has shown the importance of this period in mouse development. Removing the mother from a mouse pup or poor maternal care during this time can create anxiety for the animal later in life. But the Nature study provides a potential genetic explanation for this type of anxiety.

Dr. Hen and colleagues are now studying the effects of the loss of the receptor during early development on the integrity of anxiety circuits. Ultimately, this research could lead to new targets for drugs against anxiety.

Also participating in the study from Columbia were Dr. Cornelius Gross, a postdoctoral research fellow; Dr. Kimberly Stark, a graduate student; Dr. Xiaoxi Zhuang, formerly a postdoctoral research fellow; Dr. Sylvie Ramboz, formerly a graduate student; Dr. Ronald Oosting, formerly a postdoctoral research fellow; and from Children's Hospital of Philadelphia, Dr. Lynn Kirby, a postdoctoral research fellow, and Dr. Sheryl Beck, an associate professor of pediatrics.
The National Institute of Mental Health supported the research.

Columbia University Medical Center

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