Biology subjects

Lebel, M.

Publications and source records attributed to Lebel, M..

7 recordsLinked to original sources

bioRxiv2026

Early life stress exposure alters brain vasculature transcriptomic profiles in areas regulating stress resilience

Early life stress (ELS) events during sensitive postnatal time periods can recalibrate future stress responsiveness and precipitate mental disorders. Neurovascular adaptations can influence cognition, mood, and stress responses. Disruption of blood-brain barrier (BBB) integrity, which is formed by endothelial cells, astrocytes, and pericytes, has been implicated in affective disorders such as depression, which often arise from chronic stress experiences. Despite the BBB undergoing critical maturation stages during development, it remains poorly known how ELS influences brain vascular function, as previously shown for adult stress, and whether it augments BBB vulnerability to subsequent challenges. First, we took advantage of a public two-hit stress RNA-sequencing dataset and filtered for vascular enriched genes in the prefrontal cortex and nucleus accumbens, the two brain regions where BBB integrity is frequently compromised. This analysis revealed BBB-related gene ontology categories modulated by either ELS alone or its combination with adult stress. Then, using a mouse model combining ELS with chronic social defeat stress (CSDS) in adulthood, we found that ELS did not exacerbate CSDS susceptibility; instead, it increased social interactions and the likelihood of a resilient profile in both males and females. Transcriptomic profiling in our cohort further identified distinct sex- and region-specific BBB gene expression patterns associated with ELS and its interaction with CSDS. Additionally, we observed a reduction of corticosterone levels, the primary stress hormone, following CSDS. Altogether, these results indicate that ELS modulates stress responses when facing emotional challenges in adulthood, possibly through long-lasting changes of BBB function via the glucocorticoid system. HighlightsO_LIRNA-seq vascular filtering reveals BBB distinct ontology categories for ELS and AS C_LIO_LIELS increases the likelihood of a high social and resilient profile. C_LIO_LIPericytes gene expression associated to resilience is sex- and region-specific. C_LIO_LICORT response desensitizes after adult CSDS in both sexes. C_LI

neuroscience↗

bioRxiv2025

Multi-stage single-cell atlas of Botryllus schlosseri asexual development unveils dedifferentiating bud founder cells

Colonial tunicates are the only chordates capable of forming fully functional bodies from somatic tissues through non-embryonic development, known as budding. In Botryllus schlosseri, this agametic process, termed peribranchial budding, generates new zooids in a stereotyped, cyclical manner from a cluster of cells within the peribranchial epithelium. Despite detailed morphological characterization, the molecular and cellular underpinnings of budding initiation remain poorly understood. Here, we present the first single-cell transcriptomic atlas of B. schlosseri peribranchial budding, encompassing multiple stages from pre-budding to near-mature zooid. This high-resolution atlas captures the diversity of cell types involved in budding and their dynamics enabling precise cluster annotation and lineage trajectory inference. While circulating mesenchymal cells exhibit transcriptional hallmarks of stem-like states, we found no definitive evidence of broad contribution to bud onset and early morphogenesis beyond hematopoietic and gonadal lineages. Instead, we identified a distinct founder cell population arising from peribranchial epithelium, marked by a unique transcriptional profile and progressive acquisition of developmental potency. This supports a model in which budding is initiated by dedifferentiation of committed epithelial cells rather than activation of multi- or pluripotent stem cells. Furthermore, we highlight signaling pathways, including GNRHR-like receptors, that may couple metabolic state with developmental progression. Altogether, our data suggest that peribranchial budding in B. schlosseri is driven by potential reprogramming within epithelial tissues. This work provides a foundational resource for studying non-embryonic development and the evolution of regenerative strategies in chordates.

developmental biology↗

bioRxiv2024

First chromosome-level genome assembly of the colonial tunicate Botryllus schlosseri

Botryllus schlosseri (Tunicata) is a colonial chordate that has long been studied for its multiple developmental pathways and regenerative abilities and its genetically determined allorecognition system based on a polymorphic locus that controls chimerism and cell parasitism. We present the first chromosome-level genome assembly from an isogenic colony of B. schlosseri clade A1 using a mix of long and short reads scaf-folded using Hi-C. This haploid assembly spans 533 Mb, of which 96% are found in 16 chromosome-scale scaffolds. With a BUSCO completeness of 91.2%, this complete and contiguous B. schlosseri genome assembly provides a valuable genomic resource for the scientific community and lays the foundation for future investigations into the molecular mechanisms underlying coloniality, regeneration, histocompatibility, and the immune system in tunicates.

genomics↗

bioRxiv2023

Environmental enrichment and physical exercise prevent stress-induced behavioral and blood-brain barrier alterations via Fgf2

Chronic stress can promote loss of blood-brain barrier (BBB) integrity leading to passage of circulating inflammatory mediators in mood-regulating brain areas and establishment of depressive behaviors. Conversely, neurovascular adaptations favoring resilience to stress exposure remain undetermined. Here, we report that environmental enrichment dampens stress-induced loss of endothelial tight junction protein Claudin-5 (Cldn5) along with anxiety- and depression-like behaviors in mice via an increase in fibroblast growth factor 2 (Fgf2). Treatment of mouse and human endothelial cells with Fgf2 preceding an immune challenge with the proinflammatory cytokine TNF, elevated after chronic stress and in depression, reduces BBB dysfunction, and altered cell signaling. Coping with voluntary physical exercise also protects the BBB from stress deleterious effects by increasing Fgf2 preventing Cldn5 loss, exacerbated inflammation, and social avoidance. Circulating FGF2 level is linked with depression severity and symptomatology in humans supporting involvement of this growth factor in mood disorders and stress-induced BBB changes.

neuroscience↗

bioRxiv2022

Environmental conditions of recognition memory testing induce neurovascular changes in the hippocampus in a sex-specific manner in mice

Experiences are linked to emotions impacting memory consolidation and associated brain neuronal circuits. Posttraumatic stress disorder is an example of strong negative emotions affecting memory processes by flashbacks of past traumas. Stress-related memory deficits are also observed in major depressive disorder (MDD). We recently highlighted that sex-specific blood-brain barrier (BBB) alterations underlie stress responses in mice and human depression. However, little is known about the relationship between emotional valence, memory encoding and BBB function. Here, we investigated the effects of novel object recognition (NOR) test, an experience considered of neutral emotional valence, on BBB properties in dorsal vs ventral hippocampus in the context of various environmental conditions (arena size, handling, age). The hippocampus is a brain area central for learning and memory processes with the dorsal and ventral subregions being associated with working memory vs reference memory retrieval, respectively. Expression of genes related to BBB integrity are altered in line with learning and memory processes in a region- and sex-specific manner. We observed correlations between poor learning, anxiety, stress-induced corticosterone release and changes in BBB-associated gene expression. Comparison of BBB transcriptomes between sexes also revealed profound differences at baseline in both ventral and dorsal hippocampus. Finally, we identified circulating vascular biomarkers, such as sE-selectin and Mmp-9, altered following NOR exposure supporting that recognition memory formation has an impact on the neurovasculature. Although deemed as a neutral valence test, NOR experimental conditions impact performance, highlighting the need to minimize anxiety when performing this commonly used test in mice. Significance StatementWith this study, we aim to investigate the blood-brain barriers (BBB) role in memory acquisition and consolidation to unravel new mechanisms and decipher the involvement of non-neuronal cell types in these processes. For this purpose, male and female mice were subjected to a recognition memory test associated with a neutral emotional experience and impact on the transcriptomic profile of the BBB along with blood vascular biomarkers were evaluated under various experimental conditions. Crossing the BBB remains an important challenge to develop therapeutic drugs including in the context of memory deficits driven by psychiatric disorders or neurodegenerative diseases and thus, the possibility to directly target this barrier by better understanding its biology is attractive and innovating.

animal behavior and cognition↗

bioRxiv2022

Chronic stress exposure alters the gut barrier: sex-specific effects on microbiota and jejunum tight junctions

Major depressive disorder (MDD) is the leading cause of disability worldwide. However, 30-50% of patients are unresponsive to commonly prescribed antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis, the bidirectional communications between the central nervous system and gastrointestinal tract that are modulated by gut microorganisms, has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity, still, little is known about intestinal barrier function in these conditions particularly for the small intestine where most food and drug absorption takes place. Thus, here we investigate how chronic social or variable stress, two mouse models of depression, impact the jejunum (JEJ) intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Altered microbial populations as well as changes in gene expression of JEJ tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We took advantage of machine learning to characterize in detail morphological tight junction properties identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated if LPS injection recapitulates stress-induced changes in the JEJ and observed profound sex differences. Finally, LPS-binding protein (LBP), a marker of gut barrier leakiness, was associated with stress vulnerability in mice and translational value was confirmed on blood samples from women with MDD. Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and possibly, human depression.

neuroscience↗

bioRxiv2021

Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression.

Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.

neuroscience↗