By analyzing gene expression in human and monkey brains, scientists have discovered clusters of cells in the amygdala linked to anxiety that play unique roles, including “gatekeeper” cells that help control emotional responses. This discovery reveals potential new targets for treating anxiety disorders.
To help unravel this complex study, we’ll explore each part in detail and explain why understanding the cellular and molecular makeup of the amygdala is essential to advancing our knowledge of psychiatric and neurodevelopmental disorders.
The amygdala, a small, almond-shaped region located deep in the brain, is known to play a central role in processing emotions, particularly fear and pleasure.
It is involved in forming memories associated with emotional events and is essential for the “fight or flight” response.
Because of its role in emotional regulation and behavior, researchers have been particularly interested in studying the amygdala to understand disorders such as anxiety, depression, autism spectrum disorders (ASD), and neurodevelopmental conditions.
Theories about the function of the amygdala suggest that it may be closely linked to how psychiatric and neurodevelopmental disorders arise or progress.
However, without a clear understanding of the precise molecular and cellular makeup of the amygdala, it is challenging for scientists to create effective models or targeted treatments.
For example, knowing exactly which cells in the amygdala may be associated with anxiety or social behavior could help researchers design treatments that directly target those areas.
In this study, researchers at the University of Rochester aimed to examine the cellular structure of the amygdala and identify any unique molecular signatures that might be linked to psychiatric or neurodevelopmental disorders.
They were particularly interested in understanding how the human amygdala may differ from that of closely related species, such as rhesus monkeys.
By comparing the human amygdala with that of rhesus monkeys, the researchers hoped to determine whether the findings in these animals could be reliably applied to humans, while also identifying any uniquely human features that might be key to understanding certain disorders.
The researchers obtained amygdala tissue samples from several subregions (called “subnuclei”) of human and rhesus monkey brains. They used advanced genetic techniques, specifically single-nucleus RNA sequencing, to map gene activity in individual cells within these regions.
RNA sequencing allows scientists to see which genes are actively being used in a cell, providing a “snapshot” of that cell’s role and function based on its gene expression patterns.
A key finding of the study was the substantial diversity in cell types across different subregions of the amygdala. Even within groups of similar cells (such as neurons that activate or inhibit signals), there were significant differences depending on their exact location within the amygdala.
This variation highlights the complexity of targeting specific cell types for treatment purposes, as even small differences in cell location can impact how cells behave and contribute to emotions or disorders. A key part of the study was to compare the cellular structure and gene activity in the human amygdala with that of the rhesus monkey.
The findings suggested that while rhesus monkeys serve as a generally suitable model for studying the human amygdala, there are critical differences. One example involved a specific group of cells located in the “ventrolateral amygdala” (vLa), which was more enriched (abundant and active) in humans than in rhesus monkeys.
This group of humans contained genes potentially linked to neurodevelopmental disorders such as autism. This suggests that this group of cells may represent a unique aspect of human brain evolution, potentially providing insight into why certain psychiatric or neurodevelopmental conditions appear in humans but not in other primates.
The study also identified specific groups of cells that may be particularly relevant to understanding different disorders: Autism spectrum disorder (ASD): The vLa cell group in humans, enriched in genes associated with ASD, may represent a point of vulnerability in brain development.
Because these cells are less abundant or organized differently in monkeys, this may mean that humans are uniquely susceptible to developmental changes in this region that may contribute to ASD.
Anxiety and depression: Another group of cells expressed genes associated with “neuroticism” (a personality trait linked to mood disorders) and markers for anxiety and depressive disorders. These cells, found in an area of the amygdala containing intercalated cells, may play a role in regulating emotional responses.
Changes in these cells or their genetic expression may affect a person's susceptibility to anxiety or depressive disorders.
Neurons Brain Cells Localized Amygdala 3D
By mapping these specific cellular and molecular profiles, this study provides fundamental information that can help guide future research into targeted treatments. For example:
Targeted interventions: With a better understanding of which cells and genes are implicated in disorders such as anxiety or autism, researchers can work to develop treatments that more precisely target these areas, potentially reducing side effects and increasing efficacy.
Model validation: The findings also help validate the rhesus monkey as a model for human research, while also highlighting the limitations and unique human characteristics that must be considered.
In conclusion, this study contributes to a more detailed understanding of the cellular composition of the amygdala and identifies specific cell types that may be key in psychiatric and neurodevelopmental disorders.
By focusing on these unique gene expression clusters and patterns, the researchers have taken an important step toward bridging the gap between preclinical models and real-world human disorders.
READ MORE:
Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans
Shawn Kamboj, Erin L. Carlson, Bradley P. Ander, Kari L. Hanson, Karl D. Murray, Julie L. Fudge, Melissa D. Bauman, Cynthia M. Schumann, and Andrew S. Fox.
American Journal of Psychiatry. 30 October 2024
Abstract:
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. This study aimed to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders. 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. 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 identifies 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. 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.
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