Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by intrusive memories, hyperarousal, and avoidance behaviors triggered by exposure to traumatic events.

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in cognitive and emotional regulation, and its dysfunction has been implicated in PTSD pathogenesis.

This research article presents a cutting-edge investigation that utilizes single-nucleus transcriptome profiling to explore the neuronal gene expression mechanisms underlying PTSD stress response, with a particular focus on the 17q21.31 locus.

The study, as reported by the authors in the article with the DOI: 10.1176/appi.ajp.20220478, offers novel insights into the molecular basis of PTSD and highlights potential therapeutic targets for managing this debilitating disorder.

Introduction
Post-traumatic stress disorder (PTSD) is a severe mental health condition affecting a significant portion of the population exposed to traumatic events. Understanding the neurobiological underpinnings of PTSD is crucial for developing effective interventions and treatment strategies.

The dorsolateral prefrontal cortex (DLPFC), a region associated with executive functions and emotional regulation, has been identified as a key brain area involved in PTSD pathology.

The DLPFC also plays a role in modulating the stress response and suppressing unwanted memories. However, the molecular mechanisms underlying how the DLPFC is affected by PTSD and how it contributes to PTSD symptoms are not well understood.

This research aims to unravel the molecular mechanisms and gene expression profiles in the DLPFC that contribute to the stress response in PTSD, with a special focus on the 17q21.31 locus.

A recent study by researchers from Yale University and the VA Connecticut Healthcare System aimed to address this gap by using a novel technique called single-nucleus transcriptome profiling to examine the gene expression patterns of individual brain cells in the DLPFC of people with and without PTSD. This technique allows for a more detailed and accurate analysis of the molecular diversity and complexity of different cell types in the brain, such as neurons, astrocytes, oligodendrocytes, and microglia.

The researchers analyzed postmortem brain samples from 24 individuals who had died from non-neurological causes and had been diagnosed with PTSD or had no psychiatric history. They isolated single nuclei from the DLPFC and sequenced their RNA to measure the expression levels of thousands of genes. They then used computational methods to identify and compare different cell types and subtypes based on their gene expression profiles.

The results revealed that PTSD was associated with significant changes in gene expression in several cell types in the DLPFC, especially in neurons. The researchers found that neurons from PTSD brains showed increased expression of genes involved in synaptic transmission, neuronal excitability, and calcium signaling, suggesting enhanced neuronal activity and communication. They also found that neurons from PTSD brains showed decreased expression of genes involved in neuronal development, differentiation, and plasticity, suggesting impaired neuronal maturation and adaptation.

Moreover, the researchers identified a specific subtype of neurons that was enriched in PTSD brains and showed distinct gene expression patterns. This subtype was characterized by high expression of genes related to stress response, inflammation, and immune activation, such as CRH (corticotropin-releasing hormone), IL1B (interleukin 1 beta), and TNF (tumor necrosis factor).

These genes are known to be involved in the hypothalamic-pituitary-adrenal (HPA) axis, which is the main system that regulates the body’s response to stress. The researchers hypothesized that this subtype of neurons may represent a maladaptive stress response that contributes to PTSD symptoms.

Interestingly, the researchers also found that some of the genes that were differentially expressed in PTSD brains were located on a specific chromosomal region called 17q21.31. This region has been previously linked to increased risk for developing PTSD, as well as other psychiatric disorders such as schizophrenia and bipolar disorder.

The researchers found that 17q21.31 genes were mostly downregulated in PTSD brains, especially in neurons. Some of these genes are involved in neuronal development and function, such as KANSL1 (KAT8 regulatory NSL complex subunit 1) and MAPT (microtubule-associated protein tau). The researchers suggested that 17q21.31 genes may play a role in modulating the vulnerability or resilience to PTSD.

The study provides new insights into the molecular mechanisms underlying how PTSD affects the DLPFC and how the DLPFC influences PTSD symptoms. The study also demonstrates the power and potential of single-nucleus transcriptome profiling to reveal the cellular and molecular diversity and complexity of the human brain. The findings may have implications for developing new diagnostic tools and therapeutic strategies for PTSD and other stress-related disorders.

• Methodology: The study employed single-nucleus transcriptome profiling to analyze gene expression patterns in the DLPFC of individuals with PTSD and control subjects. Post-mortem brain tissue samples were obtained, and single-nucleus RNA sequencing (snRNA-seq) technology was utilized to characterize the transcriptional profiles of individual neurons in the DLPFC. The researchers carefully curated and processed the data to identify differentially expressed genes and uncover potential pathways associated with PTSD.
• Results: The analysis of the transcriptome data revealed significant differences in gene expression between individuals with PTSD and control subjects in the DLPFC. A cluster of genes located in the 17q21.31 locus exhibited particularly noteworthy dysregulation in PTSD cases, suggesting its involvement in the disorder’s pathophysiology. Furthermore, the researchers identified other key genes and pathways related to neuronal function, synaptic transmission, and immune response that were differentially expressed in PTSD.

reference link : https://ajp.psychiatryonline.org/doi/epdf/10.1176/appi.ajp.20220478