Biology subjects

Lax, E.

Publications and source records attributed to Lax, E..

4 recordsLinked to original sources

bioRxiv2025

Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific epigenetic and transcriptomic dynamics in the prefrontal cortex

Prenatal maternal stress (PNS) is a common early-life adversity. PNS has been linked to greater vulnerability to chronic pain in the offspring. PNS results in increased hypersensitivity after Chronic Constriction Injury (CCI) of the sciatic nerve, a common rodent model for chronic neuropathic pain. These behavioral effects are accompanied by altered levels of enzymes that regulate DNA methylation in the frontal cortex. DNA methylation, the addition of a methyl group onto cytosine bases of cytosine-guanine (CpG) sites in the genome, is an epigenetic mechanism by which life experiences can reprogram gene expression. The goal of this study was to identify differentially methylated regions that might contribute to the increased pain sensitivity following nerve injury in adulthood. Prior studies indicate widespread, sex-specific transcriptomic changes and numerous differentially methylated regions (DMRs) in the frontal cortex following PNS and nerve injury. Here we performed genome wide DNA methylation and transcriptome-wide RNAseq analysis in the frontal cortex of male and female mice that underwent PNS, CCI or both. Our analysis revealed sex-dependent changes in DNA methylation and mRNA expression, including in pathways related to neuronal and brain development, axonogenesis and synaptic regulation. The effect of DNA methylation on mRNA expression was tested in a subset of target genes. These studies suggest a role for DNA methylation in embedding increased risk for chronic pain in adulthood associated with early-life adversity.

neuroscience↗

bioRxiv2023

Poly ADP-ribosylation regulates Arc expression and promotes adaptive stress-coping

Rapid adaptation to stressful events is essential for survival and requires acute stress response and stress-coping strategy. Yet, the molecular mechanisms that govern this coping strategy have to be fully discovered. Poly ADP-ribosylation (PARylation) is a post-translational protein modification that plays a vital role in histone modification following neuronal activity and is required for long-term memory formation. Previous studies showed that inhibiting Parp1, the primary enzyme that catalyzes poly ADP-ribose polymers (PAR), impairs long-term memory formation. However, the target genes of Parp1-induced PARylation following acute stress are unknown. Here, we showed that the forced swim test, a well-established acute stress paradigm, induced elevated cortical PARylation and increased the expression of activity-dependent genes in mice. Systemic pharmacological Parp1 inhibition with ABT888 (Veliparib), impaired stress-coping in a second forced swim test done 24 hours later as measured by diminished immobility response. This effect was associated with reduced PARylation of Arc promoter and reduced Arc expression, 1 hour after Parp1 inhibition, suggesting Arc PARylation regulates its expression and hence successful stress-coping behavior.

neuroscience↗

bioRxiv2020

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

Chronic 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.

neuroscience↗

bioRxiv2018

Methyl-CpG binding domain 2 (Mbd2) deficiency causes cognitive, social and emotional functional deficits

The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2-/- mice. These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.

neuroscience↗