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Séminaire - Caroline MénardNeurovascular and immune responses in stress vulnerability, resilience and depression

Abstract :

Chronic stress is associated with neurovascular and immune changes and individual differences in these adaptations underlie resilience vs vulnerability to stress and the establishment of depressive symptoms. However to date the mechanisms by which these systems interact with the brain to induce maladaptive behaviors remain largely unknown.
The strength of our approach is a reverse translational strategy that consists in studying stress responses in mice to unravel novel biological mechanisms underlying mood disorders in humans. We combine behavioral experiments to functional, molecular and imaging studies and validate rodent findings in human samples.

We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors.

These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression. By understanding how chronic stress affects the neurovasculature and immune system we may be able to augment current antidepressant treatments or design new therapeutic strategies.

Keywords: Stress, depression, neurovascular biology, blood-brain barrier, immune system, brain plasticity, Alzheimer's disease

Selected publications

Menard C et al. (2017) Social stress induces neurovascular pathology promoting depression. Nature neuroscience, 20(12):1752-1760.

Pfau ML*, Ménard C*, Russo SJ (2018) Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities. Annual review of pharmacology and toxicology; 58:411-428.

Labonté et al. (2017) Sex-specific transcriptional signatures in human depression. Nature medicine, 23(9):1102-1111.

Ménard et al. (2017) Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience. Neuropsychopharmacology, 42(1):62-80.

Hodes et al. (2015) Neuroimmune mechanisms of depression, Nature neuroscience. 2015; 18(10):1386-93. 6) Wang et al. (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun, 2;9(1):477.