Neurobiology of resilience in depression: immune and vascular insights from human and animal studies

Dudek, Katarzyna; Dion‐Albert, Laurence; Kaufmann, Fernanda Neutzling; Tuck, Ellen; Lebel, Manon; Ménard, Caroline

doi:10.1111/ejn.14547

Cited by 100 publications

(67 citation statements)

References 417 publications

(627 reference statements)

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“…6), and indirectly with HDAC2 through HDAC1 binding, to repress gene expression (45,46). Reducing circulating proinflammatory mediators, such as cytokines, represents an attractive therapeutic approach to protect the BBB under stressful conditions (47). It will be interesting to investigate whether treatment with humanized antibodies can prevent stress-induced neurovascular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Despite clinical evidence suggesting a loss of BBB integrity in MDD nearly 35 y ago (10,47), the cellular and molecular mechanisms have remained poorly understood and causality for inappropriate coping responses under stressful conditions had yet to be confirmed. The availability of novel tools such as highresolution brain imaging, viral-mediated functional manipulations, and cell-specific transcriptomic analyses finally allows characterization of neurovascular responses in the context of chronic stress and depression in rodents and humans.…”

Section: Discussionmentioning

confidence: 99%

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Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Dudek

Dion‐Albert

Lebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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242

177

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Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Dudek

Dion‐Albert

Lebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

242

177

View full text Add to dashboard Cite

show abstract

“…MSC protective effects on the BBB may lead to a reduction in the activation of microglia and astrocytes that can modulate neuroinflammation and the development of the neurological damage [8,9]. BBB dysfunction has been correlated to the influx of proinflammatory mediators into the brain tissue and consequent depression-like behavior [54][55][56][57].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malaria

et al. 2020

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Background: Malaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient's quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression likebehavior in experimental cerebral malaria. Methods: Male C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 10 6 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 10 5 cells in 0.05 ml of saline/ mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release.

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“…The question of individual susceptibility or resilience to the pathology and sensitivity/resistance to treatments is critical. The review from Dudek et al (2019) covered the human and animal insights into the neurobiology of vulnerability versus resilience in stress and depression. They proposed strong causal links among the endocrine stress response, an exacerbated immune response and neurovascular dysfunction in depression physiopathology and resilience, highlighting the importance of sex-related differences.…”

Section: Depression In Focus: Insights From Animal and Human Data Frmentioning

confidence: 99%

Depression in focus: Insights from animal and human data, from molecular to behavioural analyses

Barrot

Yalçın

2021

Eur J of Neuroscience

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Neurobiology of resilience in depression: immune and vascular insights from human and animal studies

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 100 publications

References 417 publications

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malaria

Depression in focus: Insights from animal and human data, from molecular to behavioural analyses

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