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 3

Accelerated solute clearance in rats with compromised dcLN drainage.

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Accelerated solute clearance in rats with compromised dcLN drainage. (A ...
(A and B) Time series of representative r-flux maps from a 3 M sham rat with intact dcLN drainage (A) and a 3 M c-dcLN rat with impaired drainage (B). Positive r-flux values in red denote influx and negative r-flux values in blue indicate clearance. Note that tissue clearance in the c-dcLN rats manifests earlier (~120 min) compared with sham rats (~150 min). Scale bar: 3 mm. (C–F) Graphs showing the time trajectories of influx and clearance as fractional volumes from the brainstem and cerebellum across the 3 M sham (n = 7) and c-dcLN (n = 9) rats. The regional volume fractions of influx and clearance are shown in red and blue, respectively. (G and H) Corresponding representative r-flux maps from 10 M cohorts. (I–L) Corresponding graphs showing the time trajectories of influx and clearance as fractional volumes from the brainstem and cerebellum across the 10 M sham (n = 9) and c-dcLN (n = 11) rats. 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. For each region, P values for time × group interaction effects are indicated below the graphs; *P < 0.05, **P < 0.01, ***P < 0.001.