Summary: Researchers have identified specific cell types in the amygdala linked to anxiety, revealing potential new targets for treatment. By analyzing gene expression in human and macaque brains, scientists discovered clusters of cells with unique roles, including “gatekeeper” cells that help control emotional responses.
This insight could lead to more targeted therapies for disorders like anxiety by focusing on these critical cell types. The study emphasizes the importance of understanding cell-specific functions in the brain to address mental health disorders effectively.
Key Facts:
- Researchers found new amygdala cell types, which could lead to targeted treatments for anxiety disorders.
- FOXP2-expressing cells in the amygdala play a “gatekeeper” role, controlling emotional signal flow.
- These discoveries in both humans and macaques open avenues for translating rodent research to human anxiety treatments.
Source: UC Davis
Treating anxiety, depression and other disorders may depend on the amygdala, a part of the brain that controls strong emotional reactions, especially fear. But a deep understanding of this structure has been lacking.
Now scientists at the University of California, Davis have identified new clusters of cells with differing patterns of gene expression in the amygdala of humans and non-human primates.
The work could lead to more targeted treatments for disorders such as anxiety that affect tens of millions of people.
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.
Funding: The work was supported by the California National Primate Research Center and grants from the NIH and the Simons Foundation.
About this anxiety and neuroscience research news
Author: Andrew Fell
Source: UC Davis
Contact: Andrew Fell – UC Davis
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans” by Drew Fox et al. American Journal of Psychiatry
Abstract
Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans
Objective:
Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions.
The aim of this study was to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders.
Methods:
Tissue was dissected from multiple amygdala subnuclei in both humans (N=3, male) and rhesus macaques (N=3, male). Single-nucleus RNA sequencing was performed to characterize the transcriptomes of individual nuclei.
Results:
The results reveal substantial heterogeneity between regions, even when restricted to inhibitory or excitatory neurons. Consistent with previous work, the data highlight the complexities of individual marker genes for uniquely targeting specific cell types.
Cross-species analyses suggest that the rhesus monkey model is well-suited to understanding the human amygdala, but also identify limitations. For example, a cell cluster in the ventral lateral nucleus of the amygdala (vLa) is enriched in humans relative to rhesus macaques. Additionally, the data describe specific cell clusters with relative enrichment of disorder-related genes.
These analyses point to the human-enriched vLa cell cluster as relevant to autism spectrum disorder, potentially highlighting a vulnerability to neurodevelopmental disorders that has emerged in recent primate evolution.
Further, a cluster of cells expressing markers for intercalated cells is enriched for genes reported in human genome-wide association studies of neuroticism, anxiety disorders, and depressive disorders.
Conclusions:
Together, these findings shed light on the composition of the amygdala and identify specific cell types that can be prioritized in basic science research to better understand human psychopathology and guide the development of potential treatments.
