Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

Reis, André; Hammond, Jillian M.; Stevanovski, Igor; Arnold, Jonathon C.; McGregor, Iain S.; Gururajan, Anand

doi:10.1016/j.isci.2022.104861

Cited by 5 publications

(11 citation statements)

References 92 publications

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“…Table 2). In terms of species and sex, the seven studies conducted on animal models were performed on rodents, five using only males [47][48][49][50][51] and two including both males and females [52,53]. The two transcriptomic studies identified in humans performed both combined and sexspecific analyses.…”

Section: Resultsmentioning

confidence: 99%

“…1b; online suppl. Table 2), five using RNA sequencing [49][50][51][52][53] and two using expression arrays [47,48]. Four studies evaluated acute and chronic consequences of trauma in animalstress paradigms of PTSD [47,48,50,51].…”

Section: Animal Modelsmentioning

confidence: 99%

“…In this model, re-exposure to shock context or conditioned stimuli may reproduce PTSD symptoms [34][35][36][37]. A recent sex-specific transcriptomic study using fear conditioning as a stress paradigm and RNA sequencing examined the central and BLA in mice [53]. A total of 190 upregulated and 401 downregulated genes were reported as significant DEGs in fear-conditioned male mice.…”

Section: Transcriptomic Studiesmentioning

confidence: 99%

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Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

Núñez-Rios¹,

Martínez‐Magaña²,

Nagamatsu³

et al. 2023

Complex Psychiatry

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Introduction: Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly-understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrate brain-specific molecular findings of PTSD from humans and animals. Methods: A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms. Results: Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, 17 of them significantly enriched for PTSD. Chemical-synaptic transmission and signaling by G-protein-coupled receptors (GPCRs) were consistently enriched in across -omics and species. Discussion: Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD’s pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.

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Section: Resultsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Section: Transcriptomic Studiesmentioning

confidence: 99%

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Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

Núñez-Rios¹,

Martínez‐Magaña²,

Nagamatsu³

et al. 2023

Complex Psychiatry

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“…Other behaviours and neuronal functions in KO mice appeared normal, for example nociceptive, motor or sensory function as were levels of anxiety, unlike the features noted in P1. A recent preprint, for example, reports elevated amygdala levels of Fibcd1 mRNA in response to fear conditioning in mice (preprint: Reis et al , 2021) suggesting a potential role in anxiety yet to be delineated. We also did not detect any structural abnormalities in the brains of the Fibcd1 KO mice as was noted in P2; however, morphological alterations of the brain were not a shared feature in the two patients.…”

Section: Discussionmentioning

confidence: 99%

FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder

et al. 2022

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Whole‐exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group‐binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate‐4S (CS‐4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss‐of‐function by disrupting FIBCD1‐CS‐4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor‐related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal‐dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.

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“…Emerging evidence implicates m6A in the molecular mechanisms closely associated with synaptic connectivity and psychiatric disorders. Indeed, recent studies have shown altered m6A profiles in neurodegenerative and psychiatric disorders, including Alzheimer’s disease [ 59 , 60 , 61 ], Parkinson’s disease [ 62 ], Huntington’s disease [ 63 ], alcohol use disorder [ 64 ], and post-traumatic stress disorder (PTSD) [ 65 ] in mice and human post-mortem brains [ 22 , 23 ].…”

Section: Activity-dependent Role Of M6amentioning

confidence: 99%

Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder

Mitsuhashi

Nagy

2023

IJMS

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RNA modifications known as epitranscriptomics have emerged as a novel layer of transcriptomic regulation. Like the well-studied epigenetic modifications characterized in DNA and on histone-tails, they have been shown to regulate activity-dependent gene expression and play a vital role in shaping synaptic connections in response to external stimuli. Among the hundreds of known RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes. Through recognition of its binding proteins, m6A can regulate various aspects of mRNA metabolism and is essential for maintaining higher brain functions. Indeed, m6A is highly enriched in synapses and is involved in neuronal plasticity, learning and memory, and adult neurogenesis. m6A can also respond to environmental stimuli, suggesting an important role in linking molecular and behavioral stress. This review summarizes key findings from fields related to major depressive disorder (MDD) including stress and learning and memory, which suggest that activity-dependent m6A changes may, directly and indirectly, contribute to synaptic connectivity changes underlying MDD. Furthermore, we will highlight the roles of m6A and FTO, a m6A eraser, in the context of depressive-like behaviors. Although we have only begun to explore m6A in the context of MDD and psychiatry, elucidating a link between m6A and MDD presents a novel molecular mechanism underlying MDD pathogenesis.

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Sex-specific transcriptomic and epitranscriptomic signatures of PTSD-like fear acquisition

Cited by 5 publications

References 92 publications

Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder

Potential Roles of m6A and FTO in Synaptic Connectivity and Major Depressive Disorder

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