The Transition from Acute to Chronic Pain: Dynamic Epigenetic Reprogramming of the Mouse Prefrontal Cortex up to One Year Following Nerve Injury

AbstractChronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive and emotional information and in conditioned pain modulation. We previously reported wide-spread epigenetic reprogramming in the PFC many months following nerve injury in rodents. Epigenetic modifications, including DNA methylation, can drive changes in gene expression without modifying DNA sequences. To date, little is known about epigenetic dysregulation at the onset of acute pain or how it progresses as pain transitions from acute to chronic. We hypothesize that acute pain following injury results in rapid and persistent epigenetic remodelling in the PFC that evolves as pain becomes chronic. We further propose that understanding epigenetic remodelling will provide insights into the mechanisms driving pain-related changes in the brain. Epigenome-wide analysis was performed in the mouse PFC 1 day, 2 weeks, 6 months, and 1 year following peripheral injury using the spared nerve injury (SNI) in mice. SNI resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed between SNI and sham-operated control mice at all time points. Hundreds of differentially methylated genes were identified, including many with known function in pain. Pathway analysis revealed enrichment in genes related to stimulus response at early time points, immune function at later time points and actin and cytoskeletal regulation throughout the time course. Increased attention to pain chronicity as a factor is recommended for both pain research and management.

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Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

Cancers ◽

10.3390/cancers13143580 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3580

Author(s):

Shatavisha Dasgupta ◽

Patricia C. Ewing-Graham ◽

Sigrid M. A. Swagemakers ◽

Thierry P. P. van den Bosch ◽

Peggy N. Atmodimedjo ◽

...

Keyword(s):

Dna Methylation ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Dna Sequences ◽

Cpg Island ◽

Epigenetic Modification ◽

Vulvar Squamous Cell Carcinoma ◽

Differentially Methylated Genes ◽

Methylation Profiling

DNA methylation is the most widely studied mechanism of epigenetic modification, which can influence gene expression without alterations in DNA sequences. Aberrations in DNA methylation are known to play a role in carcinogenesis, and methylation profiling has enabled the identification of biomarkers of potential clinical interest for several cancers. For vulvar squamous cell carcinoma (VSCC), however, methylation profiling remains an under-studied area. We sought to identify differentially methylated genes (DMGs) in VSCC, by performing Infinium MethylationEPIC BeadChip (Illumina) array sequencing, on a set of primary VSCC (n = 18), and normal vulvar tissue from women with no history of vulvar (pre)malignancies (n = 6). Using a false-discovery rate of 0.05, beta-difference (Δβ) of ± 0.5, and CpG-island probes as cut-offs, 199 DMGs (195 hyper-methylated, 4 hypo-methylated) were identified for VSCC. Most of the hyper-methylated genes were found to be involved in transcription regulator activity, indicating that disruption of this process plays a vital role in VSCC development. The majority of VSCCs harbored amplifications of chromosomes 3, 8, and 9. We identified a set of DMGs in this exploratory, hypothesis-generating study, which we hope will facilitate epigenetic profiling of VSCCs. Prognostic relevance of these DMGs deserves further exploration in larger cohorts of VSCC and its precursor lesions.

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Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-020-19791-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Lanyu Zhang ◽

Tiago C. Silva ◽

Juan I. Young ◽

Lissette Gomez ◽

Michael A. Schmidt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Prefrontal Cortex ◽

Biomarker Discovery ◽

Meta Analysis ◽

Enrichment Analysis ◽

Braak Stage ◽

Polycomb Repressive Complex 2 ◽

Differentially Methylated Genes

AbstractDNA methylation differences in Alzheimer’s disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.

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Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats

Molecular Brain ◽

10.1186/s13041-020-00687-1 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Myeounghoon Cha ◽

Songyeon Choi ◽

Kyeongmin Kim ◽

Bae Hwan Lee

Keyword(s):

Chronic Pain ◽

Nerve Injury ◽

Pain Perception ◽

Imaging Techniques ◽

Insular Cortex ◽

Pain Modulation ◽

Anterior Cingulate ◽

Related Area ◽

Mtor Inhibition ◽

The Brain

AbstractNeuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

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Nerve Injury-Induced Chronic Pain Is Associated with Persistent DNA Methylation Reprogramming in Dorsal Root Ganglion

Journal of Neuroscience ◽

10.1523/jneurosci.2616-17.2018 ◽

2018 ◽

Vol 38 (27) ◽

pp. 6090-6101 ◽

Cited By ~ 22

Author(s):

Judit Garriga ◽

Geoffroy Laumet ◽

Shao-Rui Chen ◽

Yuhao Zhang ◽

Jozef Madzo ◽

...

Keyword(s):

Dna Methylation ◽

Chronic Pain ◽

Dorsal Root Ganglion ◽

Nerve Injury ◽

Dorsal Root

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Manganese-enhanced MRI depicts a reduction in brain response to nociception upon mTOR inhibition in chronic pain rats

10.21203/rs.3.rs-33778/v2 ◽

2020 ◽

Author(s):

Myeounghoon Cha ◽

Songyeon Choi ◽

Kyeongmin Kim ◽

Bae Hwan Lee

Keyword(s):

Chronic Pain ◽

Nerve Injury ◽

Pain Perception ◽

Imaging Techniques ◽

Pain Modulation ◽

Anterior Cingulate ◽

Brain Response ◽

Related Area ◽

Mtor Inhibition ◽

The Brain

Abstract Neuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn 2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

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Brainstem Pain-Modulation Circuitry and Its Plasticity in Neuropathic Pain: Insights From Human Brain Imaging Investigations

Frontiers in Pain Research ◽

10.3389/fpain.2021.705345 ◽

2021 ◽

Vol 2 ◽

Author(s):

Emily P. Mills ◽

Kevin A. Keay ◽

Luke A. Henderson

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Human Brain ◽

Brain Imaging ◽

Experimental Animal ◽

Acute Pain ◽

Behavioural Response ◽

Pain Modulation ◽

Protective Mechanism ◽

Chronic Neuropathic Pain

Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.

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Epigenetic Signatures of Early Life Adversities in Animal Models: A Role for Psychopathology Vulnerability

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.145 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S29-S29

Author(s):

M.A. Riva

Keyword(s):

Dna Methylation ◽

Prefrontal Cortex ◽

Female Rats ◽

Behavioral Alterations ◽

Bdnf Expression ◽

Adult Rats ◽

Major Mechanism ◽

Receptor Modulator ◽

Male And Female Rats ◽

Differentially Methylated Genes

Stressful experiences early in life (ELS) represent one of the most relevant factors for the vulnerability to psychopathologies. Epigenetic changes, such as DNA methylation, have emerged as a major mechanism through which ELS can alter adult behaviour leading to persistent changes of gene regulation.We performed DNA methylation analyses in the hippocampus and prefrontal cortex of adult rats exposed to stress during gestation (PNS), a model that is associated with persistent behavioral alterations relevant for psychiatric disorders.Using an epigenome-wide analysis, an overlap of 893 differentially methylated genes was observed between hippocampus and prefrontal cortex of adult male and female rats exposed to PNS. The list includes several genes previously associated with schizophrenia and other psychiatric conditions, such as calcium and potassium voltage operated channels as well as GABA and glutamate receptor subunits. By restricting the overlap to genes that were modulated in the same direction, we identified miR-30a as being less methylated in PNS rats. Interestingly one of the targets for this miRNA is the neurotrophin BDNF, whose expression was indeed reduced as a consequence of the prenatal manipulation. Interestingly chronic treatment of PNS rats with the multi-receptor modulator lurasidone during adolescence was able to prevent the changes in miR30a and BDNF expression.These results highlight the importance for the identification of methylation signatures through which stress exposure early in life could engrave on the outcome of the adult phenotype, and may allow the identification of novel genes and pathways that are affected as a consequence of ELS.Disclosure of interestM.A.R. has received compensation as speaker/consultant from Lundbeck, Otzuka, Sumitomo Dainippon Pharma and Sunovion. He has received research grants from Lundbeck, Sumitomo Dainippon Pharma and Sunovion.

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