@article{pmid40534558,

title = {Investigation of Poststroke Depression Following a Nucleus Accumbens Infarct in Mice},

author = {Jonathan Bouchard and Béatrice Daigle and Adeline Collignon and Vincent St-Arnault and Luisa Bandeira Binder and Laura Menegatti Bevilacqua and Véronique Rioux and Laurence Dion-Albert and Manon Lebel and Martin Lévesque and Michèle Desjardins and Caroline Ménard},

doi = {10.1161/STROKEAHA.125.050839},

issn = {1524-4628},

year  = {2025},

date = {2025-09-01},

journal = {Stroke},

volume = {56},

number = {9},

pages = {2772--2781},

abstract = {BACKGROUND: Poststroke depression (PSD) affects ≈33% of individuals 1 year after a stroke. Blood-brain barrier (BBB) dysfunction in the nucleus accumbens (NAc), a hub for emotional processing, reward, and mood regulation, has been linked to stress-induced depressive-like behaviors in male mice. Neurovascular alterations were also observed in postmortem tissue samples from men with a diagnosis of major depression. Thus, we aimed to investigate if BBB changes in the NAc could contribute to PSD pathophysiology.nnMETHODS: Stereotaxic injection of ET-1 (endothelin-1), a potent vasoconstrictor, was performed in the NAc of male mice to create a focal brain stroke, and then, infarct size and localization were assessed and quantified. We subsequently evaluated transcriptomic and morphological effects of the infarct on BBB-related genes and cells in the NAc, particularly those known to be altered after stress exposure in mice or human depression. BBB integrity was assessed with a dextran dye, and magnetic resonance imaging scans were conducted before versus after the injection of Gadovist, a contrast agent. Last, a battery of behavioral tests related to depressive- and anxiety-like behaviors was performed to determine if an infarct in the NAc is sufficient to induce a PSD-like phenotype.nnRESULTS: Following ET-1 injection, ≈50% of the total lesion was observed in the NAc leading to BBB hyperpermeability in this brain area. BBB gene expression was impacted by ET-1, and also surgery alone and profiles were differentially regulated throughout time up to 14 days. Gliosis in the NAc was observed with increased reactivity of astrocytes and microglia. The effect of ET-1 on PSD-like symptoms was limited. However, body weight, sociability, and activity were affected by surgery with a more pronounced impact of ET-1 on social interactions compared with naive animals.nnCONCLUSIONS: While no clear PSD phenotype was observed following an ET-1-induced stroke in the NAc of male mice, our study shed light on the technical complexity of focal lesions in deep brain structures, an understudied phenomenon occurring in humans. We provide technical insights for the development of a mouse model of deep brain lesions, characterize its impact at molecular, cellular, and behavioral levels, and highlight the need to control for vascular alterations when performing stroke surgeries.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40016352,

title = {Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood-brain barrier alterations},

author = {Katarzyna A Dudek and Sam E J Paton and Luisa Bandeira Binder and Adeline Collignon and Laurence Dion-Albert and Alice Cadoret and Manon Lebel and Olivier Lavoie and Jonathan Bouchard and Fernanda Neutzling Kaufmann and Valerie Clavet-Fournier and Claudia Manca and Manuel Guzmán and Matthew Campbell and Gustavo Turecki and Naguib Mechawar and Nicolas Flamand and Flavie Lavoie-Cardinal and Cristoforo Silvestri and Vincenzo Di Marzo and Caroline Menard},

doi = {10.1038/s41593-025-01891-9},

issn = {1546-1726},

year  = {2025},

date = {2025-04-01},

journal = {Nat Neurosci},

volume = {28},

number = {4},

pages = {766--782},

abstract = {Blood-brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39638223,

title = {Data-Driven Analysis Identifies Novel Modulation of Social Behavior in Female Mice Witnessing Chronic Social Defeat Stress},

author = {Heike Schuler and Rand S Eid and Serena Wu and Yiu-Chung Tse and Vedrana Cvetkovska and Joëlle Lopez and Rosalie Quinn and Delong Zhou and Juliet Meccia and Laurence Dion-Albert and Shannon N Bennett and Emily L Newman and Brian C Trainor and Catherine J Peña and Caroline Menard and Rosemary C Bagot},

doi = {10.1016/j.biopsych.2024.11.017},

issn = {1873-2402},

year  = {2024},

date = {2024-12-01},

journal = {Biol Psychiatry},

abstract = {BACKGROUND: Chronic social defeat stress is a widely used depression model in male mice. Several proposed adaptations extend this model to females with variable, often marginal effects. We examined if the widely used male-defined metrics of stress are suboptimal in females witnessing defeat.nnMETHODS: Using a data-driven method, we comprehensively classified social interaction behavior in 761 male and female mice after chronic social witness/defeat stress, examining social modulation of behavior and associations with conventional metrics (i.e., social interaction ratio).nnRESULTS: Social stress induced distinct behavioral adaptation patterns in defeated males and witness females. Social interaction ratio led to underpowered analyses in witness females with limited utility to differentiate susceptibility/resilience. Data-driven analyses revealed changes in social adaptation in witness females that were captured in attenuated velocity change from no target to target trials. We explored the utility of this metric in 4 female social stress models and in male witnesses. Combining social interaction ratio and velocity change optimally differentiated susceptibility/resilience in witness females and revealed resilient-specific adaptation in a resilience-associated neural circuit in female mice.nnCONCLUSIONS: Chronic witness stress induced behavioral changes in females that were qualitatively distinct from those observed in defeated males and not adequately sampled by standard male-defined metrics. Modulation of locomotion is a robust and easily implementable metric for rigorous research in witness female mice. Overall, our findings highlight the need to critically evaluate sex differences in behavior and implement sex-based considerations in preclinical model design.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38178239,

title = {Sex, hormones and cerebrovascular function: from development to disorder},

author = {Adeline Collignon and Laurence Dion-Albert and Caroline Ménard and Vanessa Coelho-Santos},

doi = {10.1186/s12987-023-00496-3},

issn = {2045-8118},

year  = {2024},

date = {2024-01-01},

journal = {Fluids Barriers CNS},

volume = {21},

number = {1},

pages = {2},

abstract = {Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood-brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis.Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands.This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38306213,

title = {Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions},

author = {Ellen Doney and Laurence Dion-Albert and Francois Coulombe-Rozon and Natasha Osborne and Renaud Bernatchez and Sam E J Paton and Fernanda Neutzling Kaufmann and Roseline Olory Agomma and José L Solano and Raphael Gaumond and Katarzyna A Dudek and Joanna Kasia Szyszkowicz and  and Manon Lebel and Alain Doyen and Audrey Durand and Flavie Lavoie-Cardinal and Marie-Claude Audet and Caroline Menard},

doi = {10.1016/j.bpsgos.2023.04.007},

issn = {2667-1743},

year  = {2024},

date = {2024-01-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {4},

number = {1},

pages = {213--228},

abstract = {BACKGROUND: Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis 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 absorption of most foods and drugs takes place.nnMETHODS: We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum 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.nnRESULTS: Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used 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 whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, 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.nnCONCLUSIONS: 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, in human depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37799760,

title = {Characterizing the blood-brain barrier and gut barrier with super-resolution imaging: opportunities and challenges},

author = {Ellen Doney and Renaud Bernatchez and Valérie Clavet-Fournier and Katarzyna A Dudek and Laurence Dion-Albert and Flavie Lavoie-Cardinal and Caroline Menard},

doi = {10.1117/1.NPh.10.4.044410},

issn = {2329-423X},

year  = {2023},

date = {2023-10-01},

journal = {Neurophotonics},

volume = {10},

number = {4},

pages = {044410},

abstract = {Brain and gut barriers have been receiving increasing attention in health and diseases including in psychiatry. Recent studies have highlighted changes in the blood-brain barrier and gut barrier structural properties, notably a loss of tight junctions, leading to hyperpermeability, passage of inflammatory mediators, stress vulnerability, and the development of depressive behaviors. To decipher the cellular processes actively contributing to brain and gut barrier function in health and disease, scientists can take advantage of neurophotonic tools and recent advances in super-resolution microscopy techniques to complement traditional imaging approaches like confocal and electron microscopy. Here, we summarize the challenges, pros, and cons of these innovative approaches, hoping that a growing number of scientists will integrate them in their study design exploring barrier-related properties and mechanisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37557079,

title = {A gut feeling: The stressed brain drives intestinal inflammation},

author = {José L Solano and Caroline Menard},

doi = {10.1016/j.immuni.2023.07.009},

issn = {1097-4180},

year  = {2023},

date = {2023-08-01},

journal = {Immunity},

volume = {56},

number = {8},

pages = {1709--1711},

abstract = {Communication between the central nervous system and the periphery contributes to stress responses and mood disorders. In a recent issue of Cell, Schneider et al. report that psychological stress exacerbates gut inflammation and dysmotility by modifying enteric glia and neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37088405,

title = {Environmental conditions of recognition memory testing induce neurovascular changes in the hippocampus in a sex-specific manner in mice},

author = {Alice Cadoret and Laurence Dion-Albert and Sara Amrani and Laurianne Caron and Mathilde Théberge and Audrey Turmel and Manon Lebel and Caroline Menard},

doi = {10.1016/j.bbr.2023.114443},

issn = {1872-7549},

year  = {2023},

date = {2023-06-01},

journal = {Behav Brain Res},

volume = {448},

pages = {114443},

abstract = {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 gene expression. 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 (HIPP) in the context of various environmental conditions (arena size, handling, age). The HIPP 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 HIPP. Finally, we identified circulating vascular biomarkers, such as sE-selectin and matrix metallopeptidase 9 (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 can shift it toward a negative valence, impacting performance and highlighting the need to minimize anxiety when performing this commonly used test in mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36805768,

title = {Neurovascular adaptations modulating cognition, mood, and stress responses},

author = {Laurence Dion-Albert and Katarzyna A Dudek and Scott J Russo and Matthew Campbell and Caroline Menard},

doi = {10.1016/j.tins.2023.01.005},

issn = {1878-108X},

year  = {2023},

date = {2023-04-01},

journal = {Trends Neurosci},

volume = {46},

number = {4},

pages = {276--292},

abstract = {The neurovascular unit (NVU) is a dynamic center for substance exchange between the blood and the brain, making it an essential gatekeeper for central nervous system (CNS) homeostasis. Recent evidence supports a role for the NVU in modulating brain function and cognition. In addition, alterations in NVU processes are observed in response to stress, although the mechanisms via which they can affect mood and cognitive functions remain elusive. Here, we summarize recent studies of neurovascular regulation of emotional processes and cognitive function, including under stressful conditions. We also highlight relevant RNA-sequencing (RNA-seq) databases aiming to profile the NVU along with innovative tools to study and manipulate NVU function that can be exploited in the context of cognition and stress research throughout development, aging, or brain disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34847973,

title = {An Indigenous Lens on Priorities for the Canadian Brain Research Strategy},

author = {Melissa L Perreault and Malcolm King and Chelsea Gabel and Christopher J Mushquash and Yves De Koninck and Ashley Lawson and Caterina Marra and Caroline Ménard and Jennie Z Young and Judy Illes},

doi = {10.1017/cjn.2021.501},

issn = {0317-1671},

year  = {2023},

date = {2023-01-01},

journal = {Can J Neurol Sci},

volume = {50},

number = {1},

pages = {96--98},

keywords = {},

pubstate = {published},

tppubtype = {article}

}