Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Nat Commun. 2022 Jan 10;13(1):164. doi: 10.1038/s41467-021-27604-x.

Abstract

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / genetics
  • Anxiety / metabolism*
  • Anxiety / pathology
  • Biological Transport
  • Biomarkers / metabolism
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Depression / genetics
  • Depression / metabolism*
  • Depression / pathology
  • Depressive Disorder, Major / genetics
  • Depressive Disorder, Major / metabolism*
  • Depressive Disorder, Major / pathology
  • E-Selectin / genetics*
  • E-Selectin / metabolism
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nucleus Accumbens / blood supply
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / pathology
  • Prefrontal Cortex / blood supply
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Sex Characteristics
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology
  • Transcriptome*

Substances

  • Biomarkers
  • E-Selectin
  • Nerve Tissue Proteins