Study of single cells in the brain show genetics may be involved in PTSD, MDD

Scientists who have analyzed the genes expressed by individual cells from the brains of people with and without post-traumatic stress disorder (PTSD) and major depressive disorders (MDD) have identified shared and unique genes expressed in these conditions.

The results, said an international team led by scientists at McLean Hospital in Massachusetts, could lead to a better understanding of the mechanisms behind these serious disorders and point to new treatment strategies. 

The findings have just been published in The American Journal of Psychiatry under the title “Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.”

Because studies have implicated the dorsolateral prefrontal cortex (DLPFC) region of the brain in PTSD and MDD, the scientists compared the genes expressed in cells in DLPFC samples collected postmortem from 11 individuals with PTSD, 10 with MDD, and 11 with none 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. through a technique called single-cell RNA sequencing.

Certain genes are expressed at varying levels

The analysis showed 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 a differential expression of genes across the study groups, and some of the genes that were identified were located in a region of chromosome #17, which has been implicated in neurodevelopmental and neurodegenerative disorders.

“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 senior author Dr. Nikolaos Daskalakis, who is head of the neurogenomics and translational bioinformatics lab at the hospital.

“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.” 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 Dr. Kerry Ressler, chief scientific officer and chief of the depression and anxiety disorders division. 

“This study is very important because it provides a glimpse into how the brains of those struggling with PTSD and depression are similar and different at the cellular and molecular level in a critical region of the brain called the dorsolateral prefrontal cortex,” commented Dr. Ned Kalin, the editor-in-chief of the journal.