Depression Isn't Just Emotional: The Cellular Origin of Depression Located in the Brain

Researchers have discovered that depression is linked to specific changes in two types of brain cells: neurons that regulate emotions and defense cells called microglia. These changes affect both communication between neurons and the control of inflammation in the brain. This shows that depression is not just emotional but involves real biological changes, paving the way for new treatments in the future.

Major depression is a complex condition that involves profound alterations in brain function, and recent advances in scientific research have helped clarify how these changes occur at the cellular and genetic level.

Large-scale studies have shown that genetic variants associated with depression are not randomly distributed in DNA, but rather concentrated in regions that control gene regulation—that is, in areas responsible for activating or silencing genetic activity.

To understand these mechanisms, scientists analyzed more than two hundred thousand cells from the dorsolateral prefrontal cortex, a brain region strongly linked to the regulation of emotions and decision-making. The brains of people with and without depression were studied using advanced techniques that allow for the examination of both DNA and RNA in individual cells.

This approach revealed which cells exhibited altered function in depression and which DNA sequences might be related to these changes.

The results pointed to two main types of affected cells. The first is a specific group of neurons called excitatory neurons, located in deep layers of the cortex. These neurons are essential for communication between different regions of the brain and for balancing emotions.

In people with depression, these neurons showed changes in chromatin accessibility, which is the way DNA is organized within the cell. This change affects the binding of transcription factors, which are proteins that regulate which genes are activated.

One of the most implicated factors was NR4A2, which responds to stressful situations. These changes can impair synaptic communication, the way neurons exchange information with each other, which is essential for maintaining a stable mood.

Image shows the layers of the cortex from superficial (L1) to deep (L6). Source: Max Planck.

The second altered cell type was a subtype of microglia, which are cells responsible for maintaining brain health, regulating inflammation, and eliminating cellular waste.

In these cells, the researchers observed a reduced accessibility of DNA regions linked to transcription factors that control the immune response. This means that depression affects not only communication between neurons, but also fundamental defense and balance processes in the nervous system.

Microglia cell

These discoveries were only possible thanks to rare collections of brain tissue donated by people with and without psychiatric conditions. The work revealed, for the first time so clearly, which specific types of brain cells are involved in depression and how genetic variations can increase the risk of the disease by disrupting both neural communication and immune defense mechanisms.

Overall, this research reinforces the idea that depression is not just an emotional or psychological issue, but rather a concrete biological condition, with real, measurable changes in the brain.

The scientists' next step is to investigate how these cellular changes affect overall brain function and, most importantly, whether targeting these specific cell types could lead to the development of more effective treatments in the future.

READ MORE:

Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression

Anjali Chawla, Doruk Cakmakci, Laura M. Fiori, Wenmin Zang, Malosree Maitra, Jennie Yang, Dariusz Żurawek, Gabriella Frosi, Reza Rahimian, Haruka Mitsuhashi, Maria Antonietta Davoli, Ryan Denniston, Gary Gang Chen, Volodymyr Yerko, Deborah Mash, Kiran Girdhar, Schahram Akbarian, Naguib Mechawar, Matthew Suderman, Yue Li, Corina Nagy, and Gustavo Turecki 

Nature Genetics, volume 57, pages 1890–1904 (2025)

DOI https://doi.org/10.1038/s41588-025-02249-4

Abstract: 

Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD.