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Life Sciences › Neuroscience › Behavioral Neuroscience
Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue
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Conflicts of Interest
Identified Weaknesses
Rating Explanation
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Paper Summary
Paperzilla title
Leaky Brain Barriers Bring the Blues: Stress Makes Female Mice (and Maybe Women) More Depressed
Chronic stress, in mouse models, leads to blood-brain barrier (BBB) alterations in the prefrontal cortex (PFC) of female mice, particularly in those susceptible to stress, marked by a decrease in the tight junction protein Claudin-5 (Cldn5). Similar changes are found in post-mortem brain tissue from women with major depressive disorder (MDD), and disrupting the BBB in female mouse PFC is sufficient to cause anxiety- and depression-like behaviors.
Possible Conflicts of Interest
None identified.
Identified Weaknesses
Heavy reliance on mouse models
The study relies heavily on mouse models, and while there are translational findings in human post-mortem tissue, the direct relevance to living human MDD needs further investigation, particularly regarding the dynamic changes in BBB permeability in response to stress and treatment.
Stress resilience as a fluid concept
Stress resilience is a complex and not fully understood phenotype, which can impact the interpretation of the findings and the differentiation between susceptible and resilient mice.
Limited brain region analysis
Focusing only on the NAc and PFC might not capture the full picture of BBB alterations in other emotion-regulation brain regions.
Lack of mechanistic detail
While the study explores some potential pathways (omega-3/omega-6, GDNF-Ret, TGFβ, Wnt), detailed mechanistic links between these pathways and Cldn5 regulation and BBB dysfunction require further investigation.
Missing positive control for BBB disruption
The study lacks a positive control group for BBB disruption, which would strengthen the causal link between Cldn5 downregulation and behavioral changes.
Confounding variable in SI test
It is not clear why the authors used a male social target for the SI test after CSDS, especially given their focus on female stress responses and the potential confounding effects of intersex social interaction.
Limited protein and functional validation
The study primarily examines transcriptional changes; further validation at the protein level and functional assays (e.g., permeability assays) would provide more comprehensive insights into BBB dysfunction.
Unclear role of estrogen
Further investigation is needed to establish the specific role of estrogen and estrogen receptors in mediating the observed sex differences in BBB alterations.
Small sample size for some experiments
The small sample size for some of the experiments (e.g., human post-mortem tissue, multiplex assays) could limit the statistical power and generalizability of the findings.
Rating Explanation
This research provides compelling evidence for the role of BBB dysfunction in stress responses and its potential contribution to MDD, particularly in females. The study utilizes a combination of mouse models, human post-mortem tissue analysis, transcriptomics, and behavioral testing, offering valuable insights into the neurovascular mechanisms underlying depression. While there are limitations related to the animal models, sample sizes, and some mechanistic details, the overall findings are strong and provide a basis for future research into novel therapeutic targets.
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File Information
Original Title:
Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue
File Name:
s41467-021-27604-x.pdf
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File Size:
7.89 MB
Uploaded:
July 14, 2025 at 11:01 AM
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