Brain's Response To Fear And Stress Influenced By Number Of Serotonin Receptors

In a localized area of the prefrontal cortex, where thought and action are orchestrated, the number and ratio of serotonin receptors were found to be directly correlated to the activity of another part of the brain called the amygdala, critical for producing emotional states such as fear. According to Ahmad Hariri, Ph.D., who led the research, these findings bring focus to what could be a fundamental factor contributing to the development of risk for psychiatric disorders and a key molecular mechanism to target as new therapies are developed.

A great deal of research has looked at the association between the amygdala and emotional behaviors and psychiatric diseases such as depression and anxiety, but relatively few studies have considered the added importance of the subgenual prefrontal cortex and its relationship to amygdala activity. The subgenual prefrontal cortex is one area where communication, or cross talk, takes place between the impulsive, reflexive amygdala and the more logical, staid prefrontal cortex.

"Our previous findings suggest that the subgenual prefrontal cortex provides an important forum for the cross talk that is necessary for regulating emotions and emotional behaviors. Now we're learning that serotonin receptors in this region are serving as important mediators in that discussion, contributing to how we will eventually behave or respond in stressful situations. It's as if they help set the tone of the discussion or determine if there will even be a discussion in the first place," explained Dr. Hariri, assistant professor of psychiatry and director of the Developmental Imaging Genomics Program at the University of Pittsburgh School of Medicine and Western Psychiatric Institute and Clinic.

Patrick M. Fisher, a research associate working with Dr. Hariri, presented the group's preliminary results involving 18 normal subjects. The study is one of the few to collect data in research subjects using two different imaging methods, allowing for more complete interpretations to be drawn about the relationship between molecular changes in the brain and differences in behavior.

Using positron emission tomography (PET), which provides three-dimensional detail of the distribution of molecular structures, the researchers were able to examine the availability of the two receptors for serotonin in specific regions of subject's brains, including the amygdala and subgenual prefrontal cortex. One of these receptors, the 5-HT1A, causes neurons to be inhibited when serotonin binds to it. In contrast, binding to the other receptor, the 5-HT2A, causes the cell to be excited.

The same subjects also underwent testing with functional magnetic resonance imaging (fMRI), which shows the areas of the brain that are engaged during different tasks. The researchers used their standard protocol whereby subjects were shown black-and-white photos depicting angry and fearful facial expressions, a simple yet highly sensitive tool that shows how the amygdala reacts to important environmental stimuli.

Those subjects in whom PET showed a higher number of serotonin 5-HT1A receptors relative to 5-HT2A receptors in the subgenual prefrontal cortex had less brain activity in this region during fMRI, as would be expected, since 5-HT1A is the inhibitory receptor. Yet, in these same subjects, the amygdala was much more stimulated than those who had a lower 5-HT1A-to-5-HT2A ratio or just more of the 5-HT2A receptors. In essence, the researchers found that these specific serotonin receptors seem to help control the extent to which any rational "discussion" takes place in the subgenual prefrontal cortex. And absent the voice of reason, the amygdala can behave as it wishes.

"With this new information about cellular and molecular structures, we're getting a more complete picture about the factors that lead to the activity of specific brain circuits that help determine emotional behavior," said Dr. Hariri.

In earlier studies, Dr. Hariri and his colleagues established the brain basis of a relationship between genetic variation and behavior. Studying people who carry a form of a gene necessary for determining expression of the serotonin transporter, who, because of this variation, are more vulnerable to develop depression in the face of stressful and difficult life circumstances, the researchers found less cross talk in the subgenual prefrontal cortex as well as greater amygdala activity.

"Genes alone do not predict behavior nor do they necessarily determine risk for disease. They simply produce the building blocks that determine the structure and function of cells, such as neurons, and the accessories involved in the function of cells, such as receptors. Of course, neurons work together as a system, and these systems of neurons operate as circuits, collectively processing information that ultimately results in a particular behavior," Dr. Hariri explained.

Based on the findings of his more recent work, Dr. Hariri plans to conduct additional studies to determine the impact this genetic variation has on individual differences in these serotonin receptors and the resulting activity of the subgenual prefrontal cortex and amygdala. Collectively, the results of such studies should provide greater understanding of the specific biological pathways, from genes to molecules to brain circuits, that contribute to risk for disease.

In addition to Dr. Hariri and Mr. Fisher, others who contributed to the research presented at the Society for Neuroscience meeting include, from the University of Pittsburgh School of Medicine, Scott K. Ziolko, Julie C. Price, Ph.D., and Carolyn C. Meltzer, M.D., department of radiology; and Eydie Moses-Kolko, M.D., and Meryl Butters, Ph.D., from the department of psychiatry. Another author, Sarah L. Berga, M.D., is now at Emory University.

The research was supported by the National Institute of Mental Health of the National Institutes of Health.