Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model
Zachary Gursky, Zohaib Nisar Khan, Sunil Koundal, Ankita Bhardwaj, Joaquin Caceres Melgarejo, Kaiming Xu, Xinan Chen, Hung-Mo Lin, Xianfeng Gu, Hedok Lee, Jonathan Kipnis, Yoav Dori, Allen Tannenbaum, Laura Santambrogio, Helene Benveniste
Zachary Gursky, Zohaib Nisar Khan, Sunil Koundal, Ankita Bhardwaj, Joaquin Caceres Melgarejo, Kaiming Xu, Xinan Chen, Hung-Mo Lin, Xianfeng Gu, Hedok Lee, Jonathan Kipnis, Yoav Dori, Allen Tannenbaum, Laura Santambrogio, Helene Benveniste
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Research Article Immunology Neuroscience

Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model

Abstract

The outflow of ‘dirty’ brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged, rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial perivenous drainage, with no evidence of hydrocephalus at any age. Surprisingly, both age groups showed enhanced brain solute clearance despite reduced glymphatic influx. CSF proteomic analysis revealed cellular stress in the form of low-grade inflammation and upregulation of pathways associated with neurodegeneration and blood brain barrier leakage in the rats with impaired lymphatic drainage. Our findings highlight that dcLN drainage is indeed a prerequisite for normal cerebral homeostasis in the rat and reveal the brain’s age-dependent compensatory responses to chronic impairment of its lymphatic drainage pathways.

Authors

Zachary Gursky, Zohaib Nisar Khan, Sunil Koundal, Ankita Bhardwaj, Joaquin Caceres Melgarejo, Kaiming Xu, Xinan Chen, Hung-Mo Lin, Xianfeng Gu, Hedok Lee, Jonathan Kipnis, Yoav Dori, Allen Tannenbaum, Laura Santambrogio, Helene Benveniste

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Figure 1

Evidence of dcLN drainage impairment in young and middle-aged rats.

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Evidence of dcLN drainage impairment in young and middle-aged rats. (A) ...
(A) Schematic overview of the experimental design. (B and C) Drainage to deep cervical lymph nodes (dcLN, dashed outlines) of 3 month old (3 M) rats after sham (B) or c-dcLN surgery (C). (D and E) Corresponding data from 10 M rats. Scale bars: 2 mm. (F) Drainage streams along the internal carotid artery (iCA) and external carotid artery (eCA). The dcLN is located immediately lateral to the common carotid artery (CCA). Aff, afferent; Eff, efferent lymphatic vessels. (G) Corresponding data from a 3 M c-dcLN rat in which drainage along the iCA and eCA is sustained, although the dcLN is gone. (H and I) Corresponding sham and c-dcLN data from 10 M rats. Scale bars: 2 mm. (J and K) Time signal curves (TSC) of drainage along the eCA (J) and iCA (K) from 3 M cohorts. Corresponding graphs of drainage along the eCA and iCA from the 10M cohorts. Data are presented as mean and 95% CIs. A linear mixed model for repeated measures with (FDR) correction for multiple comparisons was utilized to assess differences across groups. P values for time × group interaction effects are indicated on the graphs. Note that drainage along the eCA of 10 M c-dcLN rats is increased compared with sham rats. *P < 0.05. Corresponding graphs of drainage along the eCA and iCA from the 10M cohorts (L and M).