Biology subjects

Darcq, E.

Publications and source records attributed to Darcq, E..

4 recordsLinked to original sources

bioRxiv2025

IFNγ-associated immune--metabolic remodeling drives serotonin-kynurenine imbalance with cortical vulnerability in lupus-prone mice

IntroductionNeuropsychiatric systemic lupus erythematosus (NPSLE) is a major clinical challenge, characterized by heterogeneous manifestations and the absence of reliable biomarkers. The mechanisms linking systemic autoimmunity to neuronal injury and neuropsychiatric symptoms remain poorly understood. MethodsUsing the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mapping, cortical metabolomics, and behavioral analyses to dissect immune-metabolic-neuronal interactions. ResultsInflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as the central driver. Composite cytokine scores correlated strongly with plasma NfL, establishing an immune-neuronal injury axis. Region-resolved analyses revealed distinct CNS cytokine signatures, including selective hippocampal loss of interleukin-10 and IFN{gamma}-dominated responses in the frontal cortex. Cortical metabolomics demonstrated diversion of tryptophan metabolism away from serotonin toward the kynurenine pathway, with increased quinolinic acid/kynurenic acid (QA/KA) ratio and upregulation of indoleamine 2,3-dioxygenase-1 (Ido1) and kynurenine 3-monooxygenase (Kmo). NfL levels were negatively associated with serotonin and positively with 3-hydroxykynurenine and QA/KA, linking axonal damage to an excitotoxic metabolic environment. Importantly, cortical serotonin levels correlated with exploratory behavior, linking serotonergic depletion to anxiety-like phenotypes. DiscussionTogether, these results delineate a cascade in which systemic IFN{gamma} is associated with cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood or CSF monitoring of IFN{gamma}, NfL, and kynurenine metabolites could represent a candidate biomarker framework for NPSLE. However, validation in independent patient cohorts will be essential, and therapeutic modulation of IDO1/KMO or serotonergic pathways remains an avenue for future investigation.

immunology↗

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

Striatal Mu-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of {micro}-opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse. HighlightsO_LIRepeated administration of morphine potentiates IPSCdMSN{lozenge}GPh neurotransmission. C_LIO_LIRepeated administration of fentanyl potentiates IPSCdMSN{lozenge}SNc neurotransmission. C_LIO_LIFentanyl withdrawal induces negative emotional states, which drive relapse. C_LI

neuroscience↗

bioRxiv2021

Neurons expressing mu opioid receptors of the habenula promote negative affect in a projection-specific manner

BACKGROUNDThe mu opioid receptor (MOR) is central to hedonic balance, and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, and notably the medial habenula (MHb) where the receptor is highly dense, however this was not investigated. Our prior data suggest that the inhibitory activity of MOR in the MHb limits aversive states. Here we therefore tested the hypothesis that neurons expressing MOR in the MHb (MHb-MOR neurons) promote negative affective states. METHODSUsing Oprm1-Cre knock-in mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of MHb-MOR neuron stimulation in approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze and marble burying) and despair-like behavior (tail suspension). RESULTSOpto-stimulation of MHb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus (IPN), MHb-MOR neurons project to the dorsal raphe nucleus (DRN), uncovering a yet unreported connection of MHb to a main mood center. Opto-stimulation of MHb-MOR/IPN neurons triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of MHb-MOR/DRN neurons increased levels of anxiety with no effect on other behaviors, revealing two dissociable pathways controlling negative affect. CONCLUSIONSThis study demonstrates aversive activity of MHb neurons that respond to MOR opioids. We propose that inhibition of these neurons by endogenous or exogenous opioids relieves negative affect via two distinct MHb microcircuits, contributing to despair-like behavior (MHb-MOR/IPN) and anxiety (MHb-MOR/DRN). This mechanism has implications for hedonic homeostasis and addiction.

neuroscience↗