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<p>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 <i>Cnr1</i> 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 <i>Cnr1</i> in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of <i>CNR1</i> in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.</p>

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Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月27日

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

摘要

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.