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Post-Traumatic Stress Disorder and Depression: The Molecular Changes That Shape the Brain


Researchers have examined the relationship between brain changes and blood proteins in over 50,000 participants from the UK Biobank, and found significant correlations and similarities between shared and specific brain and blood markers in post-traumatic stress disorder and major depressive disorder, highlighting potential biomarkers and therapeutic targets.


Stress-related disorders such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) result from a complex interplay between genetic factors and lifelong exposure to stress.


These interactions lead to epigenetic modifications in the human genome, altering gene and protein expression, which may contribute to the development of these disorders.


Previous studies of brain samples from deceased individuals, focusing on post-traumatic stress disorder and major depressive disorder, have revealed some genetic similarities and sex differences, as well as the involvement of immunological and neuronal mechanisms.


However, these studies have generally been limited to a single layer of biological analysis, which has prevented a broader and more integrated understanding of the molecular underpinnings of these disorders.

To overcome these limitations, researchers from the Broad Institute of MIT and Harvard University created a comprehensive database by analyzing multiple brain regions and using a multiomics approach.


They studied the brains of individuals with post-traumatic stress disorder, major depressive disorder, and neurotypical controls (231 participants in total, with 77 in each group).


They focused on three brain regions: the central nucleus of the amygdala (CeA), the medial prefrontal cortex (mPFC), and the dentate gyrus of the hippocampus (DG).

They examined changes in RNA (transcriptomic), DNA methylation (methylomic) and protein (proteomic) levels in these areas. They complemented these analyses with single-nuclear RNA sequencing (snRNA-seq), genetics and protein studies in blood plasma, seeking an integrated perspective of the biological systems involved in PTSD and MDD.


snRNA-seq (single-nuclear RNA sequencing) is a sequencing technique that allows detailed analysis of the transcriptome in individual cells, with a specific focus on RNA present in the nucleus.


This technique provides in-depth insight into the transcription and gene regulation processes occurring within the nucleus, providing valuable information that is often not captured in other sequencing approaches.

The snRNA-seq process begins with the isolation of cell nuclei. To do this, the cells are subjected to a lysis process, which breaks the cell membrane and releases the nucleus, preserving the nuclear RNA.


This step is crucial, especially in complex or fragile tissues, where complete dissociation of the cells can damage or lose important information.


Once isolated, the nuclei are processed to extract the RNA contained within them, which includes both messenger RNA (mRNA) and other types of nuclear RNA that have not yet been fully processed.


After RNA extraction, the genetic material is converted to complementary DNA (cDNA) and sequenced using next-generation sequencing (NGS) technologies.


This sequencing allows the quantification of gene expression at a highly detailed, cell-by-cell level, enabling the analysis of which genes are active and how they are being regulated.


One of the main advantages of snRNA-seq is its ability to preserve the cellular context. This is particularly useful in studies involving difficult-to-dissociate tissues, such as the brain, or fixed and frozen samples.


In addition, this technique allows the study of early gene regulation, since it analyzes RNA while still in the nucleus, capturing transcripts that may not be present in the cytoplasm.


snRNA-seq is widely applied in research on diseases, cellular development and differentiation. For example, in disease research, this technique helps identify changes in the transcriptome that may be associated with conditions such as cancer, neurological disorders and inflammatory diseases.

It is also used to explore how gene expression is regulated during development and cellular differentiation.


The results revealed that most molecular changes were observed in the mPFC, where differentially expressed genes and their exons showed the strongest signs of disease. However, altered methylation was most evident in the dentate gyrus of the hippocampus of individuals with PTSD and in the central nucleus of the amygdala of individuals with MDD.


DNA methylation is a chemical process in which methyl groups (a carbon atom bonded to three hydrogen atoms) are added to DNA, usually at the 5-position of the cytosine ring, one of the four bases of DNA.


This process does not alter the DNA sequence, but it can influence how genes are expressed. DNA methylation acts as a kind of “tag” that can turn genes on or off, regulating their activity without modifying the underlying genetic sequence.


This mechanism is essential for normal processes such as development, cellular differentiation, and the maintenance of cellular identity. However, alterations in methylation may be associated with several diseases, including cancer, where normal methylation patterns are often disrupted, leading to inappropriate gene activation or repression.

These findings were confirmed through replication analyses using multi-omics data from two additional cohorts. Moderate overlap between the two disorders was also found, with childhood trauma and suicide being significant drivers of molecular variation in both. Sex-specific differences were more evident in MDD.


Molecular pathway analyses linked disease-associated alterations to immune mechanisms, metabolism, mitochondrial function, neuronal regulation, and stress hormone signaling.


Key regulators identified included genes and factors such as IL1B, GR, STAT3, and TNF.


Through multi-omics and genetic network analyses, the researchers identified underlying elements of the disorders, suggesting the influence of aging-related processes, inflammation, and stress.


To complement these findings, the researchers also performed snRNA-seq analyses in the dorsolateral prefrontal cortex, revealing differentially expressed genes, dysregulated pathways, and regulators in different cell types, both neuronal and non-neuronal.


These findings included genes related to stress and brain function. When they examined the relationship between brain changes and proteins in the blood in more than 50,000 participants from the UK Biobank, they found significant correlations and similarities between brain and blood markers.


Mapping results from genome-wide association studies (GWAS) for PTSD and MDD showed limited overlap between genetic risk and disease processes, at both the gene and pathway levels.

Systems biology dissection of PTSD and MDD. The interplay between genetic susceptibility and stress exposure, occurring both early and late in life, contributes to the pathogenesis of stress-related disorders and their progression from diagnosis to death. This integrative systems approach combines multi-region, multi-omic analyses with single-nucleus transcriptomics, blood plasma proteomics, and GWAS-based fine mapping to provide deeper insights into molecular mechanisms associated with risk and those involved in the disease process.


Ultimately, the researchers prioritized genes with multi-omic and multi-trait associations, those involved in multiple biological layers (such as DNA, RNA, proteins) and that influence multiple traits or characteristics in health or disease conditions, many of which are part of specific pathways or networks, show potential as blood-based biomarkers, or are involved in genetic risk for PTSD and MDD.


These findings provide a detailed understanding of shared and specific molecular dysregulations in PTSD and MDD, reveal the involvement of specific cell types, and highlight potential biomarkers and therapeutic targets.



READ MORE:


Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

NIKOLAOS P. DASKALAKIS, ARTEMIS IATROU, CHRIS CHATZINAKOS, 

AARTI JAJOO, CLARA SNIJDERS, DENNIS WYLIE, CHRISTOPHER P. DIPIETRO, IOULIA TSATSANI, CHIA-YEN CHEN, AND KERRY J. RESSLER et al.

SCIENCE, 24 May 2024, Vol 384, Issue 6698

DOI: 10.1126/science.adh3707


Abstract:


The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

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© 2024 by Lidiane Garcia

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