The roots of fear: Understanding the amygdala

The work is published Oct. 30 in the American Journal of Psychiatry.

"The amygdala is central to emotion processing in the brain, and is known to contribute to fear and anxiety," said Drew Fox, associate professor in the UC Davis Department of Psychology and senior author on the paper.

For that 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's increasingly clear that the overall size and structure of the amygdala is not a good predictor of emotional problems in life, Fox said.

Recently, research in rodents has shown that each subregion of the amygdala contains many different cell types with distinct and sometimes opposing functions.

"This suggests that disorders emerge from alterations in specific cell types with distinct roles," Fox said. However, it is challenging to identify such cell types in humans or other primates, leaving the cellular landscape of the primate amygdala largely unexplored.

To address this critical knowledge gap, graduate student Shawn Kamboj led a collaboration between Fox's research group and the lab of Professor Cynthia Schumann at the UC Davis School of Medicine to identify cell types in subregions of the human and non-human primate amygdala, based on the genes they express. This could advance basic research by making it easier to translate results between rodents, non-human primates and humans, and open up new targets for treatment.

Single cell RNA sequencing

The researchers took samples from brains of humans and rhesus macaque monkeys, separated individual cells and sequenced their RNA. This shows which genes are active (being expressed) in a particular cell and allows researchers to sort them into groups based on gene expression.

"We can cluster cells based on their gene expression, identify cell types and their developmental origin," Fox said.

The researchers searched for specific cell types that expressed the genes implicated in anxiety and other disorders in humans. This strategy can help identify cell types that are most likely to give rise to psychopathology, Fox said.

For example, they identified a specific group of cells that expressed a gene called FOXP2. The new study shows that in humans and macaques, FOXP2 is expressed in cells on the edges of the amygdala, called intercalated cells. Excitingly, researchers have demonstrated that in rodents, this small group of FOXP2-expressing cells play a role as "gatekeepers," controlling signal traffic in or out of the amygdala. Together, these data suggest intercalated cells to be a potentially powerful avenue for developing treatments.

The researchers were also able to identify both similarities and differences between cell types in the human and non-human primate amygdala. 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 that can be targeted by drugs, called Neuropeptide FF Receptor 2 (NPFFR2). This result can guide the development of new treatment strategies, by suggesting drugs that activate the NPFFR2 pathway as a potential treatment target in relation to anxiety-related disorders.

Anxiety is a complicated disorder that can present in many different ways. With a better understanding of the cell types involved, it may be possible to identify and target "chokepoints" that affect large numbers of people who experience extreme and debilitating anxiety, Fox said.

"Put simply, if we're developing a drug to target the amygdala, we want to know which cell type we are targeting," he said.

Additional authors on the paper are: Erin Carlson, Kari Hanson and Bradley Ander, UC Davis MIND Institute; Julie Fudge, University of Rochester; Melissa Bauman, California National Primate Research Center; Karl Murray, UC Davis School of Medicine. The work was supported by the California National Primate Research Center and grants from the NIH and the Simons Foundation.