Treatment for anxiety, depression and other disorders may depend on the amygdala, a part of the brain that controls strong emotional responses, particularly fear. Until now, however, there has been a lack of in-depth understanding of this structure. Now, scientists at the University of California, Davis, have identified new cell clusters with distinct gene expression patterns in the amygdala of humans and non-human primates. The work could lead to more targeted treatments for disorders such as anxiety disorders that affect millions of people. The findings were published in the American Journal of Psychiatry.

Disorders Caused by Changes in Certain Cell Types of the Amygdala

“The amygdala is central to emotion processing in the brain and is known to contribute to fear and anxiety,” said Drew Fox, an associate professor in the Department of Psychology at UC Davis and senior author of the paper. For this reason, there has long been interest in whether variations in the size or structure of the amygdala are related to disorders such as anxiety and depression. However, it is becoming increasingly clear that the overall size and structure of the amygdala is not a good predictor of emotional problems in life. Recent research in rodents has revealed that each subregion of the amygdala contains many different cell types with diverse and sometimes opposing functions. This suggests that disturbances arise from changes in specific cell types with distinct roles.

To address this critical knowledge gap, PhD student Shawn Kamboj spearheaded a collaboration between Fox’s research group and the laboratory of Professor Cynthia Schumann at the UC Davis School of Medicine to identify cell types in subregions of the amygdala of humans and nonhuman primates based on the genes they express. This could advance basic research by facilitating the transfer of results between rodents, non-human primates and humans, and opening up new treatment targets.

Development of New Treatment Strategies

The researchers took samples from the brains of humans and rhesus monkeys, separated individual cells and sequenced their RNA. This shows which genes are active (expressed) in a particular cell and allows the researchers to sort them into groups based on gene expression. The researchers looked for specific cell types that expressed genes associated with anxiety and other disorders in humans. This strategy can help identify cell types most likely to give rise to psychopathological disorders, Fox said. For example, they identified a particular group of cells that expressed a gene called FOXP2. The new study shows that in humans and macaques, FOXP2 is expressed in cells at the edges of the amygdala called intercalated cells. Excitingly, researchers have demonstrated that this small group of FOXP2-expressing cells serve as “gatekeepers” in rodents, controlling signaling traffic into and out of the amygdala. Taken together, these data suggest that intercalated cells are a potentially promising target for treatment development.

The researchers were also able to identify similarities and differences between cell types in the amygdala of humans and non-human primates. This is important for understanding how discoveries in animal models of disorders such as anxiety and autism relate to humans. The approach could help identify cell types as potential drug targets. For example, FOXP2-expressing cells tend to express both anxiety-related genes and a receptor, the neuropeptide FF receptor 2 (NPFFR2), that can be affected by medication. This finding can guide the development of new treatment strategies by suggesting drugs that activate the NPFFR2 signaling pathway as a potential treatment target for anxiety-related disorders. Anxiety is a complicated disorder that can present itself in many different ways. With a better understanding of the cell types involved, it may be possible to identify and target “bottlenecks” that affect a large number of people suffering from extreme and debilitating anxiety.