MeCP2 mediates transgenerational transmission of chronic pain.
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ABSTRACT:
SUBMITTER: Tao W
PROVIDER: S-EPMC8367090 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy between experienced chronic low back pain (CBP) intensity (twice daily ratings) and remembered pain intensity (n = 48 subjects) relative to psychometric properties, hippocampus morphology, memory capabilities, and personality traits related to reward. 77% of CBP patients exaggerated remembered pain, which depended on their strongest experienced pain and their most recent mood rating. This bias persisted over nearly 1 year and was related to reward memory bias and loss aversion. Shape displacement of a specific region in the left posterior hippocampus mediated personality effects on pain memory bias, predicted pain memory bias in a validation CBP group (n = 21), and accounted for 55% of the variance of pain memory bias. In two independent groups (n = 20/group), morphology of this region was stable over time and unperturbed by the development of chronic pain. These results imply that a localized hippocampal circuit, and personality traits associated with reward processing, largely determine exaggeration of daily pain experiences in chronic pain patients.
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Project description:Although joint pain in rheumatoid arthritis (RA) is conventionally thought to result from inflammation, arthritis pain and joint inflammation are at least partially uncoupled. This suggests that additional pain mechanisms in RA remain to be explored. Here we show that Fc?RI, an immune receptor for IgG immune complex (IgG-IC), is expressed in a subpopulation of joint sensory neurons and that, under naïve conditions, Fc?RI crosslinking by IgG-IC directly activates the somata and peripheral terminals of these neurons to evoke acute joint hypernociception without obvious concurrent joint inflammation. These effects were diminished in both global and sensory neuron-specific Fcgr1 knockout mice. In murine models of inflammatory arthritis, Fc?RI signaling was upregulated in joint sensory neurons. Acute blockade or global genetic deletion of Fcgr1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without measurably altering joint inflammation. Conditional deletion of Fcgr1 in sensory neurons produced similar analgesic effects in these models. We therefore suggest that Fc?RI expressed in sensory neurons contributes to arthritis pain independently of its functions in inflammatory cells. These findings expand our understanding of the immunosensory capabilities of sensory neurons and imply that neuronal Fc?RI merits consideration as a target for treating RA pain.
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Project description:Previous studies have suggested that astrocyte activation in the spinal dorsal horn may play an important role in the development of chronic neuropathic pain; but the mechanisms involved in astrocyte activation and their modulatory effects remain unknown. The inward rectifying potassium channel protein 4.1 (Kir4.1) is the most important background K+ channel in astrocytes. However, how Kir4.1 is regulated and contributes to behavioral hyperalgesia in chronic pain is unknown. In this study, single-cell RNA sequencing analysis indicated that the expression of Kir4.1 and Methyl-CpG-binding protein 2 (MeCP2) were both decreased in spinal astrocytes after chronic constriction injury (CCI) in a mouse model. Conditional knockout of the Kir4.1 channel in spinal astrocytes led to hyperalgesia; and overexpression of the Kir4.1 channel in spinal cord relieved CCI-induced hyperalgesia. Expression of spinal Kir4.1 after CCI was regulated by MeCP2. Electrophysiological recording in spinal slices showed that knockdown of Kir4.1 significantly regulated the excitability of astrocytes and then functionally changed the firing patterns of neurons in dorsal spinal cord. Therefore, targeting spinal Kir4.1 maybe an underlying treatment for hyperalgesia in chronic neuropathic pain.
2022-07-24 | GSE208766 | GEO
Project description:IntroductionVeterans with chronic pain frequently report comorbid disruptions in sleep and psychological dysfunction. The purpose of this study was to investigate whether psychological function variables mediate the sleep-pain relationship. Knowledge regarding such contributing factors can inform the development and optimization of treatments for sleep disturbances and pain.Materials and methodsIn an IRB-approved, registered clinical trial, we collected objective sleep data from U.S. military Veterans with chronic pain (N = 184, ages 23-81) using wrist actigraphy for 7 days and self-reported survey data assessing sleep quality, pain intensity, and psychological function (depression, anxiety, post-traumatic stress disorder, and pain catastrophizing). We investigated the associations between objectively measured and self-reported sleep quality and self-reported pain intensity. In addition, using parallel mediation analyses, we examined whether psychological function variables mediated these associations.ResultsActigraphy showed suboptimal sleep duration (less than 7 hours) and sleep fragmentation for most participants. Self-reported poor sleep quality and pain intensity were significantly correlated. Pain catastrophizing was found to mediate the association between self-reported sleep quality and pain intensity.ConclusionsSleep disturbances in this sample of Veterans with chronic pain included insufficient sleep, fragmented sleep, and perceived poor sleep quality. Analyses suggest that poor perceived sleep quality and pain intensity are mediated via pain catastrophizing. The finding highlights the potential importance of pain catastrophizing in Veterans with chronic pain. Future longitudinal research is needed to determine the extent to which treatments that reduce pain catastrophizing might also improve both sleep and pain outcomes.
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Project description:G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8-37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8-37-cholestanol, but not unconjugated CGRP8-37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8-37-cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund's adjuvant more effectively than unconjugated CGRP8-37 Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention.
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Project description:Environmental stresses experienced by individual parents can influence offspring phenotypes in ways that enhance survival under similar conditions. Although such adaptive transgenerational plasticity is well documented, its transmission mechanisms are generally unknown. One possible mechanism is environmentally induced DNA methylation changes. We tested this hypothesis in the annual plant Polygonum persicaria, a species known to express adaptive transgenerational plasticity in response to parental drought stress. Replicate plants of 12 genetic lines (sampled from natural populations) were grown in dry versus moist soil. Their offspring were exposed to the demethylating agent zebularine or to control conditions during germination and then grown in dry soil. Under control germination conditions, the offspring of drought-stressed parents grew longer root systems and attained greater biomass compared with offspring of well-watered parents of the same genetic lines. Demethylation removed these adaptive developmental effects of parental drought, but did not significantly alter phenotypic expression in offspring of well-watered parents. The effect of demethylation on the expression of the parental drought effect varied among genetic lines. Differential seed provisioning did not contribute to the effect of parental drought on offspring phenotypes. These results demonstrate that DNA methylation can mediate adaptive, genotype-specific effects of parental stress on offspring phenotypes.
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Project description:IntroductionRecent advances regarding mechanisms of chronic pain emphasize the role of corticolimbic circuitry in predicting risk for chronic pain, independently from site of injury-related parameters. These results compel revisiting the role of peripheral nociceptive signaling in chronic pain. We address this issue by examining what brain circuitry transmit information regarding the intensity of chronic pain and how this information may be related to a common co-morbidity, depression.MethodsResting state functional MRI was used in a large group of chronic pain patients (n=40 chronic back pain, CBP, and n=44 osteoarthritis, OA patients), and in comparison to healthy subjects (n=88). We used a graph theoretical measure, degree count, to investigate voxel-wise information sharing/transmission in the brain. Degree count, a functional connectivity based measure, identifies the number of voxels functionally connected to every given voxel. Subdividing the chronic pain cohort into discovery, replication, and also for overall group we show that only degree counts of diencephalic voxels centered in the ventral lateral thalamus reflected intensity of chronic pain, independently of depression.ResultsPain intensity was reliably associated with degree count of the thalamus, which was correlated negatively with components of the default mode network and positively with the periaqueductal grey (in contrast to healthy controls). Depression scores were not reliably associated with regional degree count.ConclusionCollectively the results suggest that, across two types of chronic pain, nociceptive specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pro-nociceptive descending modulation, and interrupting cortical cognitive processes.
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Project description:Transgenerational epigenetic inheritance results from incomplete erasure of parental epigenetic marks during epigenetic reprogramming at fertilization. The significance of this phenomenon, and the mechanism by which it occurs, remains obscure. Here, we show that genetic mutations in Drosophila may cause epigenetic alterations that, when inherited, influence tumor susceptibility of the offspring. We found that many of the mutations that affected tumorigenesis induced by a hyperactive JAK kinase, Hop(Tum-l), also modified the tumor phenotype epigenetically, such that the modification persisted even in the offspring that did not inherit the modifier mutation. We analyzed mutations of the transcription repressor Krüppel (Kr), which is one of the hop(Tum-l) enhancers known to affect ftz transcription. We demonstrate that the Kr mutation causes increased DNA methylation in the ftz promoter region, and that the aberrant ftz transcription and promoter methylation are both transgenerationally heritable if Hop(Tum-l) is present in the oocyte. These results suggest that genetic mutations may alter epigenetic markings in the form of DNA methylation, which are normally erased early in the next generation, and that JAK overactivation disrupts epigenetic reprogramming and allows inheritance of epimutations that influence tumorigenesis in future generations.
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Project description:RNA sequencing of N2 worms. Heterochromatic repetitive DNA transmits environmentally-acquired information for up-to fourteen generations in C. elegans
2017-04-24 | GSE83528 | GEO
Project description:Epigenetics, or regulation of gene expression independent of DNA sequence, is the missing link between genotype and phenotype. Epigenetic memory, mediated by histone and DNA modifications, is controlled by a set of specialized enzymes, metabolite availability, and signaling pathways. A mostly unstudied subject is how sub-toxic exposure to several xenobiotics during specific developmental stages can alter the epigenome and contribute to the development of disease phenotypes later in life. Furthermore, it has been shown that exposure to low-dose xenobiotics can also result in further epigenetic remodeling in the germ line and contribute to increase disease risk in the next generation (multigenerational and transgenerational effects). We here offer a perspective on current but still incomplete knowledge of xenobiotic-induced epigenetic alterations, and their possible transgenerational transmission. We also propose several molecular mechanisms by which the epigenetic landscape may be altered by environmental xenobiotics and hypothesize how diet and physical activity may counteract epigenetic alterations.
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