Woman with depression with head in hands
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Links between genes in excitatory (EX) and inhibitory (IN) neurons and astrocytes were found through an international study of gene expression in post-traumatic stress and major depressive disorders (PTSDs and MDDs). The authors say it was the first study to analyze PTSD pathology at single-cell resolution and could lead to novel markers for these conditions and new therapeutic targets.

The study was led by investigators at McLean Hospital and analyzed the genes expressed in approximately 575,000 human brain cells. The findings appear July 26 in The American Journal of Psychiatry. The senior author is Nikolaos P. Daskalakis, director of Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital.

“Our findings can be used in the development of PTSD and MDD biomarkers to detect people at risk for the disorder since we linked the identified brain profiles with genetic risk. Excitingly, we have also associated our findings with brain imaging biomarkers that can be measured in patients to monitor disease status,” said Daskalakis.

Previous studies have implicated the dorsolateral prefrontal cortex (DLPFC) region of the brain in PTSD and MDD. But most studies of these conditions have relied on bulk-tissue RNA sequencing. Single-cell RNA-seq, these authors say, is needed to dissect cell-type-specific mechanisms.

This team compared the genes expressed in cells in DLPFC samples collected postmortem from 11 individuals with PTSD, 10 with MDD, and 11 without either of these conditions with a replication dataset half the size.

The researchers detected which genes were expressed by which cells—including eight different types of cells, using single-cell RNA sequencing. They found that certain genes are expressed at varying levels in DLPFC neurons and astrocytes (a type of cell that supports neurons) depending on whether an individual had PTSD, MDD, or neither condition. For example, differential gene expression indicated increased glucocorticoid signaling in the brains of people with PTSD.

Various other pathways also had differential expression of genes across the study groups, suggesting that these pathways may be dysregulated in MDD or PTSD. Some of the genes that were identified were located in a region of chromosome 17 that has been implicated in neurodevelopmental and neurodegenerative disorders.

“Our findings can also be used in the development of targeted treatments with cell type resolution. The observation of the neuronal glucocorticoid signaling pathway involvement means that neuron-specific glucocorticoid-based treatments could be developed compared with the current glucocorticoid treatments that affect most cell types, making them not specific and prone to side effects,” said Daskalakis.

Next steps that could bring this research closer to the clinic include studies involving stem cell–derived cells.

“Stem cell–derived cells exposed to stress agents could recapitulate brain stress pathology. Additional research could involve genetic and pharmacologic manipulations of these cells to study mechanisms and develop therapies,” said co-author Kerry J. Ressler, chief scientific officer and chief of the Division of Depression and Anxiety Disorders at McLean Hospital.

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