Transcriptomics of the depressed and PTSD brain

Zhang, Jing; Kaye, Alfred; Wang, Jiawei; Girgenti, Matthew J.

doi:10.1016/j.ynstr.2021.100408

Cited by 8 publications

(5 citation statements)

References 139 publications

(166 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our findings, bulk-tissue 9 and single-nucleus 20 RNA-seq in the DLPFC revealed downregulation of genes associated with inflammatory cytokines, microglia– activation, and immune-signaling pathways in MDD. Some studies in rodents 84,90 and humans 91 have likewise suggested suppression of microglial immune-response in chronic stress-induced disorders. Furthermore, recent reports provide evidence at gene-expression 9,10,20,75 and protein levels 10,88,92 for a non-inflammatory microglial phenotype in MDD.…”

Section: Discussionmentioning

confidence: 96%

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Chawla,

Cakmakci,

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

Major depressive disorder (MDD) associated genetic variants reside primarily in the non-coding, regulatory genome. Here we investigate genome-wide regulatory differences and putative gene-regulatory effects of disease risk-variants by examining chromatin accessibility combined with single-cell gene-expression profiles in over 200,000 cells from the dorsolateral prefrontal cortex (DLPFC) of 84 individuals with MDD and neurotypical controls. MDD-associated accessibility alterations were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of nuclear receptor (NR)4A2, an activity-dependent TF responsive to pathological stress. The same neurons were significantly enriched for MDD-associated genetic variation disrupting cis-regulatory sites and TF binding associated with genes involved in synaptic communication. Furthermore, a grey matter microglial cluster exhibited differentially closed chromatin in MDD affecting binding sites bound by TFs known to regulate immune homeostasis. In summary, our study points to specific cell types and regulatory mechanisms whereby genetic variation may increase predisposition to MDD.

show abstract

Section: Discussionmentioning

confidence: 96%

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Chawla,

Cakmakci,

Zhang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Finally, while immunofluorescence of epigenetic markers is more often used to draw preliminary conclusions about changes in transcriptional processes (Chouliaras et al, 2013, Demyanenko andUzdensky, 2019), it is not possible to draw a one-to-one relationship between the observed differences in HDAC2, 5mC and 5hmC levels and actual alterations in histone acetylation and gene expression. Different studies have shown transcriptional alterations in response to stress (Floriou-Servou et al, 2018), and in PTSD specifically , Zhang et al, 2021, but it would require future studies to causally link such changes to the alterations in histone acetylation, DNA methylation and hydroxymethylation that have been observed.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal trauma memory processing conveying susceptibility to traumatic stress

Dirven,

Melis,

Daneva

et al. 2024

Preprint

View full text Add to dashboard Cite

While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted- Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma- related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal PV+neuronal density and a relatively lower activity of PV+interneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.

show abstract

“…The study was concordant with Girgenti et al who performed a transcriptome-wide analysis on 4 dorsal PFC subregions (including the dlPFC) of individuals with PTSD ( Girgenti et al, 2021 ). Zhang et al (2021) emphasized in their review, both PTSD and MDD have a GABAergic interneuron transcriptional dysregulation; however, PTSD and MDD share few DEGs, suggesting that the dysregulation occurs in different subpopulations of GABAergic interneurons. These results reflect the heterogeneity in cell population and cell function in the brain and suggest that future transcriptomic wide studies using droplet-based single cell genomics to study RNA expression at the single cell and/or single nucleus level would be beneficial.…”

Section: Brain Molecular Studies Of Stress-related Disordersmentioning

confidence: 99%