Biology subjects

Lutz, P.-E.

Publications and source records attributed to Lutz, P.-E..

8 recordsLinked to original sources

bioRxiv2026

Sex differences in epigenetic mechanisms of chronic pain-induced depression

Chronic pain is a major risk factor for depression, yet the molecular mechanisms underlying this comorbidity remain poorly understood, particularly in women. To address this gap, we systematically investigated sex differences in the epigenomic adaptations associated with chronic pain-induced depressive-like behaviors. Neuropathic pain was induced in the mouse using the sciatic nerve cuff model, and molecular analyses were performed in the anterior cingulate cortex (ACC), a key brain region implicated in both pain and affective processing. We profiled genome-wide DNA methylation, three histone modifications (H3K27ac, H3K4me1, and H3K27me3), and gene expression using EM-seq, Cut&Tag sequencing, and RNA-seq, respectively. Differential analyses were conducted for each molecular layer and integrated through gene co-expression network analysis. We found that chronic pain induced extensive remodeling of DNA methylation and histone modification landscapes in both sexes. Strikingly, these changes occurred at largely distinct genomic loci in males and females, revealing pronounced sex-specific epigenetic responses. Despite this divergence, the affected regions displayed similar regulatory organization, including enrichment at shared genic features, transcription factor binding sites, and chromatin profiles. Importantly, these adaptations converged on partly overlapping genes, biological pathways, and co-expression modules across sexes. The most affected gene modules were predominantly associated with synapse-related processes, consistent with previous knowledge, and were closely connected to modules enriched for epigenetic regulatory functions. Together, these findings indicate that chronic pain engages sex-specific epigenetic mechanisms that ultimately converge on common functional outcomes. Such convergence highlights the potential value of targeting sex-specific epigenetic substrates in future therapeutic strategies.

neuroscience↗

bioRxiv2025

The DNA methylation enzymatic machinery in substance use disorders: a systematic review

Substance use disorders (SUD) are chronic affections defined by similar symptoms across a variety of psychoactive drugs, including alcohol, cocaine, opioids, or methamphetamine. Epigenetic mechanisms such as DNA methylation represent key candidates to help explain the long-lasting effect of these drugs, as well as inter-individual variation in vulnerability. Here, we systematically reviewed current knowledge on the role of DNA methylation and the related enzymatic machinery in rodent models of SUD. Using a prospectively registered methodology, 99 articles were prioritized. A first set of studies manipulated the expression or activity of methylation or demethylation pathways. Depending on the brain region or drug considered, SUD-related behavioral and molecular manifestations were bidirectionally modulated, suggesting both pathogenic and protective roles for drug-induced methylomic plasticity. A second set of articles focused on candidate genes. Although significant heterogeneity across experimental models, brain regions or gene targets resulted in an absence of replicated findings, available data nevertheless support the notion that drugs of abuse trigger DNA methylation changes at discrete loci. Third, recent genome-wide studies have started to demonstrate that these drugs recruit widespread reprogramming. Strikingly, most adaptations occur outside promoter regions, highlighting an important challenge toward their functional interpretation. Finally, studies of drug exposure during gestation or adolescence suggest long-lasting consequences, with the potential for early intervention.

neuroscience↗

bioRxiv2025

Sex-divergent brain epigenetic reprogramming by chronic opioids

Opioid use disorder (OUD) is a chronic condition that exhibits sex differences in prevalence, symptoms and treatment. Yet, the epigenetic mechanisms underlying these differences remain largely unknown. Here, we investigated the nucleus accumbens, a key brain region in OUD, to define the multiomic consequences of chronic morphine exposure in male and female mice. We profiled DNA methylation, five histone post-translational modifications, and their transcriptional effects at bulk and cell-type-specific levels. Despite comparable tissue organization and neurophysiological responses to morphine, epigenetic adaptations occurred at highly sex-specific genomic loci. These adaptations nevertheless followed common mechanistic principles, acting at similar gene features and transcription factor binding sites across sexes. Strikingly, they converged on overlapping genes, biological functions, and co-expression modules, and partially recapitulated transcriptional signatures of OUD in men and women. Therefore, our findings uncover a profound epigenetic sex divergence that mediates convergent biological dysregulation, and highlight opportunities for developing improved therapeutic strategies tailored to sex-specific mechanisms.

neuroscience↗

bioRxiv2022

Functional genomic mechanisms of opioids: a systematic review of animal and human studies

In the past two decades, over-prescription of opioids for pain management has driven a steep increase in opioid use disorder (OUD) and death by overdose, exerting a dramatic toll on western countries. OUD is a chronic relapsing disease associated with a lifetime struggle to control drug consumption, suggesting that opioids trigger long-lasting brain adaptations, notably through functional genomic and epigenomic mechanisms. Current understanding of these processes, however, remain scarce, and have not been previously reviewed systematically. To do so, the goal of the present work was to synthesize current knowledge on genome-wide transcriptomic and epigenetic mechanisms of opioid action, in primate and rodent species. Using a prospectively registered methodology, comprehensive literature searches were completed in PubMed, Embase, and Web of Science. Of the 2709 articles identified, 73 met our inclusion criteria and were considered for qualitative analysis. Focusing on the 5 most studied nervous system structures (nucleus accumbens, frontal cortex, whole striatum, dorsal striatum, spinal cord; 44 articles), we also conducted a quantitative analysis of differentially expressed genes, in an effort to identify a putative core transcriptional signature of opioids. Only one gene, Cdkn1a, was consistently identified in eleven studies, and globally, our results unveil surprisingly low consistency across published work, even when considering most recent single-cell approaches. Analysis of putative sources of variability detected significant contributions from species, brain structure, duration of opioid exposure, strain, time-point of analysis, and batch effects, but not type of opioid. To go beyond those limitations, we leveraged threshold-free methods to illustrate how genome-wide comparisons may generate new findings and hypotheses. Finally, we discuss current methodological development in the field, and their implication for future research and, ultimately, better care.

neuroscience↗

bioRxiv2022

The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain

While depression and chronic pain are frequently comorbid, underlying neuronal circuits, and their relevance for the understanding of psychopathology, remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. In naive animals, we demonstrate that activation of this pathway is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, a hub gene significantly upregulated in both mice and humans in the context of altered mood, is necessary for the emergence of depressive-like behaviors. Overall, these results place the BLA-ACC pathway at the core of pain and depression comorbidity, and unravel the role of impaired myelination and Sema4a in mood control.

neuroscience↗

bioRxiv2020

Increased functional coupling of the mu opioid receptor in the anterior insula of depressed individuals

The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N=95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.

neuroscience↗

bioRxiv2019

Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides

Glial dysfunction is a major feature in the pathophysiology of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) cell functions have been associated with depression, the crosstalk between these two major glial cell types has never been assessed in that context. AS are potent regulators of OL cells and myelination, in part through gap junction-mediated intercellular communication made possible by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins, allowing cytosolic transport and metabolic support to OL cells. Because changes in the expression of AS-specific connexins have been previously reported in the brain of depressed individuals, this study aimed at addressing the integrity of AS-OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of the AS-specific Cx30 in the ACC, and mapped its expression onto oligodendrocyte somas and myelinated axons as well as brain vasculature in post-mortem brain samples from depressed suicides (N=48) and matched controls (N=23). The differential gene expression of key components of the gap junction nexus was also screened through RNA-sequencing dataset previously generated by our group, and validated by quantitative real-time PCR. Our results indicate that Cx30 expression mapping to OL cells is selectively decreased in depressed suicides, an effect that was associated with decreased expression of OL-specific connexins Cx32 and Cx47, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking and function of gap junction channels. These results provide a first evidence of impaired gap junction mediated communication between astrocytes and oligodendrocytes in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.

neuroscience↗

bioRxiv2018

Non-CG methylation and multiple epigenetic layers associate child abuse with immune and small GTPase dysregulation

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we described molecular cross-talk among multiple epigenetic mechanisms, including 6 histone marks, DNA methylation and the transcriptome, in subjects with a history of ELA and controls. We first uncovered, in the healthy brain, previously unknown interactions among epigenetic layers, in particular related to non-CG methylation in the CAC context. We then showed that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicated that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides new insights into epigenetic brain regulation as a function of early-life experience.

neuroscience↗