Timing of Chemical Signal Critical for Normal Emotional Development

A signaling protein suspected of malfunctioning in anxiety and mood disorders plays a key role in the development of emotional behavior, report researchers funded by the National Institute of Mental Health. Mice lacking it in frontal brain circuits during an early critical period fail to develop normal reactions in anxiety-producing situations. 

Rene Hen, Ph.D., Columbia University, and colleagues created mice that lacked the protein, which brain cells use to receive signals from the chemical messenger serotonin, by knocking-out the gene that codes for it. As adults, these "knockout" mice were slow to venture into - or eat in - unfamiliar environments. By selectively restoring, or "rescuing" certain populations of the receptor proteins, the researchers have now pinpointed when and where they enable the brain to cope with anxiety. Hen, Cornelius Gross, Ph.D., Xiaoxi Zhuang, Ph.D, and colleagues report on their discovery in the March 28, 2002 Nature.

Brain neurons communicate with each other by secreting messenger chemicals, such as serotonin, which cross the synaptic gulf between cells and bind to receptors on neighboring cell membranes. Medications that enhance such binding of serotonin to its receptor (serotonin selective reuptake inhibitors, or SSRIs) are widely prescribed to treat anxiety and depression, suggesting that the receptor plays an important role in regulating these emotions.

Behavior of the animals in the study mimicked human anxiety. The mice bred not to express the gene that codes for the serotonin receptor (5-HT1A) moved around less than normal animals in open spaces, balked at entering elevated mazes, and were slower to begin eating in such novel environments. Yet, the researchers didn't know which of two populations of serotonin receptors - one in the forebrain and another deep in the brainstem - was responsible. To find out, they crossed the receptor knockout mice with mice engineered to turn receptor expression on and off in specific brain regions. This gave birth to a line of transgenic animals in which only the forebrain receptors were rescued from the gene knockout. This "rescue" line of mice behaved normally when tested for the anxiety-like behaviors, suggesting a key role for the receptor in forebrain circuits mediating anxiety.

Next, the researchers treated adult mice - knockout, rescue, and normal - with a drug (doxycycline) that shuts off receptor expression. Even without the receptors, the adult rescue mice continued to show normal anxiety-like behavior. The researchers inferred that the receptor "functions earlier in development to establish normal adult anxiety-like behavior."

To find out when this occurs, they gave the receptor-abolishing drug to breeding pairs of rescue mice to turn off receptor expression in their pups during the embryonic and early postnatal period. As adults, these offspring behaved just as anxiously as knockout mice when tested. This, together with the timing of receptor expression in the rescue mice, suggested that the critical period for establishing normal anxiety-like behavior is between 5 and 21 days after birth.

Serotonin stimulation of the forebrain receptor during this period likely triggers "long lasting changes in brain chemistry or structure that are essential for normal emotional behavior throughout life," suggest the researchers. They note a number of studies pointing to such a role for serotonin during this critical time.

Intrigued by evidence that the serotonin receptor may be abnormal in patients with panic disorder and post-traumatic stress syndrome, other NIMH-supported researchers are embarking on brain imaging studies of its function in these anxiety disorders.

The current study was supported under a NIMH grant on the biology of serotonin to Irwin Lucki, Ph.D., University of Pennsylvania. Also participating were: Kimberly Stark, Ph.D., Sylvie Ramboz, Ph.D., Ronald Oosting, Ph.D., Luca Santarelli, M.D., Columbia University; Lynn Kirby, Ph.D., Sheryl Beck, Ph.D., Children's Hospital of Philadelphia.

The National Institute of Mental Health (NIMH) is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.