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For someone with anxiety disorder, giving a public presentation, going to the doctor, or taking a school test can cause sweaty palms, shortness of breath, and a racing heartbeat that can be debilitating. But the dread of the present and the future for anxiety sufferers apparently is rooted in the past.

New findings from Columbia University Health Sciences researchers and colleagues elsewhere reveal that the circuitry in the brain that leads to later anxiety first gets established in early development.

The 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, describes a window of time during mouse development—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, supported by the National Institute of Mental Health and led by Dr. Rene Hen, associate professor of pharmacology (in psychiatry and in the Center for Neurobiology and Behavior), focused on the serotonin-5HT1A receptor gene. The researchers manipulated the time in the brain that the receptor was active to understand its role in creating anxiety circuitry.

Brain neurons communicate by secreting chemical messengers—neurotransmitters, such as serotonin—that cross the synaptic gulf between nerve cells and bind to receptors on neighboring nerve cell membranes. Once neurotransmitters bind to 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) effectively treat anxiety and depression, suggesting the receptor and the neurotransmitter play a role in regulating these emotions. Since the drugs act by increasing serotonin in the brain, scientists have presumed the disorders may be due to decreased serotonin levels in the adult brain.

Mice who live all their lives without the gene for the serotonin-5HT1A receptor, so-called knock-out 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 environments.

Through sophisticated genetic tools, the researchers 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 could then monitor the resulting anxiety-like behaviors in the animals.

First, they identified brain locations important for the anxious behavior. When they shut off receptor activity in one part of the brain without 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 shut off receptor activity 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 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. 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.


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