Date of Award

January 2024

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Erica Herzog


The choroid plexus (ChP) secretes a half-liter/day of cerebrospinal fluid (CSF) and is the blood-CSF barrier with critical immune functions. Hydrocephalus, commonly caused by infection or hemorrhage, lacks non-surgical treatments due to obscure pathobiology. We hypothesize that in acquired hydrocephalus, the dual ChP functions of CSF secretion and blood-CSF barrier maintenance become pathologically entangled in a maladaptive disease state. To test this hypothesis, we created novel rat models of post-infectious (PIH) and posthemorrhagic hydrocephalus (PHH) and conducted a multi-omics investigation of these animals to dissect the cellular, molecular, and physiological pathology underlying PIH and PHH . Our systems approach combined functional genomics to characterize the ChP immune response, including the first-ever single-cell transcriptomic profile of the ChP in a pathological condition, as well as in vivo assessments of ChP secretory capacity and CSF dynamics to systematically characterize fluid homeostasis. Integrated multi-omic analysis of diverse post-infectious (PIH) and post-hemorrhagic (PHH) hydrocephalus models show lipopolysaccharide and blood products, respectively, trigger highly similar Tlr4-dependent immune-secretory responses at the ChP-CSF interface. Activated ChP macrophages elicit a CSF “cytokine storm” that stimulates CSF production from ChP epithelial cells via a kinase-regulated multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents acute PIH and PHH by antagonizing ChP-mediated CSF hypersecretion. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related neuroinflammatory disorders, and identify a druggable target of ChP immune-secretory function.


This is an Open Access Thesis.

Open Access

This Article is Open Access